Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer

ABSTRACT

The invention relates to a pharmaceutical dosage form having a breaking strength of at least 300 N and comprising a pharmacologically active compound, an anionic polymer bearing carboxylic groups, wherein the content of the anionic polymer is ≧20 wt.-%, based on the total weight of the pharmaceutical dosage form, and a nonionic surfactant.

This application is a continuation of U.S. application Ser. No.13/778,186, filed Feb. 27, 2013, which claims priority of U.S.Provisional Patent Application No. 61/603,986, filed on Feb. 28, 2012,and European Patent Application No. 12 001 301.6, filed on Feb. 28,2012, the entire contents of which patent applications are incorporatedherein by reference.

The invention relates to a pharmaceutical dosage form having a breakingstrength of at least 300 N and comprising a pharmacologically activecompound, an anionic polymer bearing carboxylic groups, wherein thecontent of the anionic polymer is 20 wt.-%, based on the total weight ofthe pharmaceutical dosage form, and a nonionic surfactant.

Tamper-resistant pharmaceutical dosage forms containingpharmacologically active compounds have been known for many years.Pharmacologically active compound abuse with conventional dosage formsis typically achieved by (i) pulverization of the pharmaceutical dosageform and nasal administration of the powder; (ii) pulverization of thepharmaceutical dosage form, dissolution of the powder in a suitableliquid and intravenous administration of the solution; (iii)pulverization of the pharmaceutical dosage form and inhalation bysmoking; (iv) liquid extraction of the drug from the pharmaceuticaldosage form and intravenous administration of the solution; and thelike. Accordingly, many of these methods of abuse require the mechanicaldestruction of the pharmaceutical dosage form in order to render itsuitable for abuse.

In the past several different methods have been developed to avoid drugabuse.

Some of these concepts of rendering pharmaceutical dosage forms tamperresistant rely on the mechanical properties of the pharmaceutical dosageforms, particularly a substantially increased breaking strength(resistance to crushing). The major advantage of such pharmaceuticaldosage forms is that comminuting, particularly pulverization, byconventional means, such as grinding in a mortar or fracturing by meansof a hammer, is impossible or at least substantially impeded. Thus, byconventional means that are available to an abuser, such pharmaceuticaldosage forms cannot be converted into a form suitable for abuse, e.g. apowder for nasal administration. In this regard it can be referred toe.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO2006/082099, and WO 2008/107149.

These known tamper resistant pharmaceutical dosage forms, however, arenot satisfactory in every respect.

The tamper resistance of these known pharmaceutical dosage formssubstantially relies on the presence of high molecular weightpolyalkylene oxide, in particular polyethylene oxide, as matrixmaterial, and further depends on the manufacturing process. In order toachieve a high breaking strength, the manufacturing process typicallyincludes the application of heat and pressure to a preformed mixturecomprising polyalkylene oxide and pharmacologically active substance,and requires careful selection of the process conditions.

In tablet formulations, acrylic acid polymers (carbomers) are used inconcentrations up to 10 wt.-% as dry or wet binders and as ratecontrolling agents. It is known from WO 2006/082099, that small amountsof anionic methacrylic acid and methyl methacrylate copolymers(Eudragit®) can be included into polyalkylene oxide matrices oftamper-resistant dosage forms without altering their mechanicalproperties. However, pharmaceutical dosage forms comprising largeramounts of anionic polymer(s) that nonetheless exhibit a sufficientlyhigh breaking strength and impact resistance are not known so far.

T. Ozeki et al., International Journal of Pharmaceutics, 165 (1998)239-244 disclose poly(ethylene oxide)-carboxyvinylpolymer soliddispersions prepared from water/ethanol mixture as a solvent. Similarly,T. Ozeki et al., Journal of Controlled Release, 63 (2000) 287-295relates to controlled release from solid dispersion composed ofpoly(ethylene oxide)-Carbopol® interpolymer complex with variouscross-linking degrees of Carbopol®. The polyethylene oxide employed inthese studies had an average molecular weight of below 150,000 g/molonly. However, these solid dispersions are prepared by means of wetgranulation using water/ethanol as the granulating fluid, and are thusnot suitable for the avoidance of drug abuse.

US 2008/069871 discloses oral dosage forms of therapeutic agents thatare resistant to abuse and methods of their formulation. In particular,oral dosage forms that are resistant to dissolution in aqueous solutionsof ethanol are described.

EP 1 502 592 relates to controlled release oxycodone dosage form fororal administration to human patients, comprising an oxycodone salt; amatrix incorporating said oxycodone salt; the matrix comprising at leastone acrylic resin; wherein said dosage form has an in vitro dissolutionrate when measured by the USP Paddle Method at 100 rpm in 900 ml aqueousbuffer (pH between 1.6 and 7.2) at 37 DEG C, between 12.5% and 42.5% (byweight) oxycodone salt released after 1 hour, between 25% and 56% (byweight) oxycodone salt released after 2 hours, between 45% and 75% (byweight) oxycodone salt released after 4 hours and between 55% and 85%(by weight) oxycodone salt released after 6 hours, the in vitrodissolution rate being independent of pH between 1.6 and 7.2.

US 2007/190142 discloses a dosage form and method for the delivery ofdrugs, particularly drugs of abuse, characterized by resistance tosolvent extraction, tampering, crushing, or grinding, and providing aninitial burst of release of drug followed by a prolonged period ofcontrollable drug release.

US 2011/097404 relates to an oral dosage form comprising (i) an opioidagonist in releasable form and (ii) a sequestered opioid antagonistwhich is not released when the dosage form is administered orallyintact.

WO 2010/140007 discloses a dosage form, particularly a tamper resistantdosage form, comprising: melt-extruded particulates comprising a drug;and a matrix; wherein said melt-extruded particulates are present as adiscontinuous phase in said matrix.

US 2011/159100 relates to controlled release formulations and methodsfor preparing controlled release formulations for delivery of activedrug substances. The formulations may be employed to producepharmaceutical compositions, such as controlled release dosage forms,adjusted to a specific administration scheme.

WO 2012/028318 discloses a pharmaceutical dosage form exhibiting abreaking strength of at least 500 N, said dosage form containing—apharmacologically active ingredient (A); —a physiologically acceptablepolymer (B) obtainable by polymerization of a monomer compositioncomprising an ethylenically unsaturated monomer bearing an anionicfunctional group, in protonated form or a physiologically acceptablesalt thereof; —a polyalkylene oxide (C) having a weight averagemolecular weight of at least 200,000 g/mol, wherein the content of thepolyalkylene oxide (C) is at least 20 wt.-%, based on the total weightof the dosage form; wherein the pharmacologically active ingredient (A)is present in a controlled-release matrix comprising the polymer (B) andthe polyalkylene oxide (C).

There is a demand for tamper resistant pharmaceutical dosage formscontaining pharmacologically active compounds that have advantagescompared to the tamper resistant pharmaceutical dosage forms of theprior art.

This object has been achieved by the subject-matter describedhereinbelow.

A first aspect of the invention relates to a pharmaceutical dosage formhaving a breaking strength of at least 300 N and comprising

-   -   a pharmacologically active compound,    -   an anionic polymer bearing carboxylic groups, wherein the        content of the anionic polymer is 20 wt.-%, based on the total        weight of the pharmaceutical dosage form, and    -   a nonionic surfactant.

It has been surprisingly found that tamper-resistant pharmaceuticaldosage forms having a high breaking strength and impact resistance canbe prepared by using an anionic polymer and optionally a nonionicsurfactant, and that the presence of high molecular weight polyalkyleneoxide is not required. Furthermore, it has been surprisingly found thatliquid extraction of the pharmacologically active compound andsubsequent administration of the thus obtained liquid by thenon-prescribed, parenteral route can be substantially impeded byincorporating an effective amount of anionic polymer and optionallynonionic surfactant into the pharmaceutical dosage forms. It has furtherbeen found that these ingredients can have a stabilizing effect on thepharmaceutical ingredient contained in the dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in greater detail with reference tothe drawings, wherein:

FIGS. 1-A, 1-B, 1-C, 1-D and 1-E, respectively, show the correspondingforce-displacement diagrams of examples I-1, I-2, I-3, I-4 and C.

The pharmaceutical dosage form according to the invention comprises apharmaceutically active compound, preferably a pharmacologically activecompound having psychotropic activity, more preferably an opioid.Preferably, the pharmacologically active compound is selected from thegroup consisting of opiates, opioids, stimulants, tranquilizers, andother narcotics.

For the purpose of the specification, the term pharmacologically activecompound also includes the free base and the physiologically acceptablesalts thereof.

According to the ATC index, opioids are divided into natural opiumalkaloids, phenylpiperidine derivatives, diphenylpropylaminederivatives, benzomorphan derivatives, oripavine derivatives, morphinanderivatives and others. Examples of natural opium alkaloids aremorphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine,diamorphine, papaveretum, and codeine. Further pharmacologically activecompounds are, for example, ethylmorphine, hydrocodone, oxymorphone, andthe physiologically acceptable derivatives thereof or compounds,preferably the salts and solvates thereof, preferably the hydrochloridesthereof, physiologically acceptable enantiomers, stereoisomers,diastereomers and racemates and the physiologically acceptablederivatives thereof, preferably ethers, esters or amides.

The following opiates, opioids, tranquilizers or other narcotics aresubstances with a psychotropic action, i.e. have a potential of abuse,and hence are preferably contained in the pharmaceutical dosage formaccording to the invention: alfentanil, allobarbital, allylprodine,alphaprodine, alprazolam, amfepramone, amphetamine, amphetaminil,amobarbital, anileridine, apocodeine, axomadol, barbital, bemidone,benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine,butobarbital, butorphanol, camazepam, carfentanil,cathine/D-norpseudoephedrine, chlordiazepoxide, clobazam clofedanol,clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine,codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam,desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide,diamorphone, diazepam, dihydrocodeine, dihydromorphine, dihydromorphone,dimenoxadol, dimephetamol, dimethylthiambutene, dioxaphetylbutyrate,dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine,ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene,etorphine, faxeladol, fencamfamine, fenethylline, fenpipramide,fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam,halazepam, haloxazolam, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, hydroxymethylmorphinan, ketazolam,ketobemidone, levacetylmethadol (LAAM), levomethadone, levorphanol,levophenacylmorphane, levoxemacin, lisdexamfetamine dimesylate,lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam,mefenorex, meperidine, meprobamate, metapon, meptazinol, metazocine,methylmorphine, metamphetamine, methadone, methaqualone,3-methylfentanyl, 4-methylfentanyl, methylphenidate,methylphenobarbital, methyprylon, metopon, midazolam, modafinil,morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine,nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol,normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam,oxycodone, oxymorphone, Papaver somniferum, papaveretum, pernoline,pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphane,phenazocine, phenoperidine, piminodine, pholcodeine, phenmetrazine,phenobarbital, phentermine, pinazepam, pipradrol, piritramide, prazepam,profadol, proheptazine, promedol, properidine, propoxyphene,remifentanil, secbutabarbital, secobarbital, sufentanil, tapentadol,temazepam, tetrazepam, tilidine (cis and trans), tramadol, triazolam,vinylbital, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide,(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)propionate,(RR—SS)-2-acetoxy-4-trifluoro-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, andcorresponding stereoisomers, in each case the corresponding derivativesthereof, physiologically acceptable enantiomers, stereoisomers,diastereomers and racemates and the physiologically acceptablederivatives thereof, e.g. ethers, esters or amides, and in each case thephysiologically acceptable compounds thereof, in particular the acid orbase addition salts thereof and solvates, e.g. hydrochlorides.

In a preferred embodiment the pharmaceutical dosage form according tothe invention contains an opioid selected from the group consisting ofDPI-125, M6G (CE-04-410), ADL-5859, CR-665, NRP290 and sebacoyldinalbuphine ester.

Particularly preferred pharmacologically active compounds includehydromorphone, oxymorphone, oxycodone, tapentadol, and thephysiologically acceptable salts thereof. In a preferred embodiment thepharmaceutical dosage form according to the invention contains onepharmacologically active compound or more pharmacologically activecompounds selected from the group consisting of oxymorphone,hydromorphone and morphine. In another preferred embodiment, thepharmacologically active compound is selected from the group consistingof tapentadol, faxeladol and axomadol.

In still another preferred embodiment, the pharmacologically activecompound is selected from the group consisting of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole,particularly its hemicitrate;1,1-[3-dimethylamino-3-(2-thienyl)-pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]indole,particularly its citrate; and1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyrano[3,4-b]-6-fluoroindole,particularly its hemicitrate. These compounds are known from, e.g., WO2004/043967, WO 2005/066183.

The pharmacologically active compound may be present in form of aphysiologically acceptable salt, e.g. physiologically acceptable acidaddition salt.

Physiologically acceptable acid addition salts comprise the acidaddition salt forms which can conveniently be obtained by treating thebase form of the active ingredient with appropriate organic andinorganic acids. Active ingredients containing an acidic proton may beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. The termaddition salt also comprises the hydrates and solvent addition formswhich the active ingredients are able to form. Examples of such formsare e.g. hydrates, alcoholates and the like.

The content of the pharmacologically active compound in thepharmaceutical dosage form is not limited. The pharmacologically activecompound is present in the pharmaceutical dosage form in atherapeutically effective amount. The amount that constitutes atherapeutically effective amount varies according to the activeingredients being used, the condition being treated, the severity ofsaid condition, the patient being treated, and whether thepharmaceutical dosage form is designed for an immediate or retardedrelease.

Preferably, the content of the pharmacologically active compound iswithin the range of from 0.01 to 80 wt.-%, more preferably 0.1 to 50wt.-%, still more preferably 1 to 25 wt.-%, based on the total weight ofthe pharmaceutical dosage form. In a preferred embodiment, the contentof pharmacologically active compound is within the range of from 7±6wt.-%, more preferably 7±5 wt.-%, still more preferably 5±4 wt.-%, 7±4wt.-% or 9±4 wt.-%, most preferably 5±3 wt.-%, 7±3 wt.-% or 9±3 wt.-%,and in particular 5±2 wt.-%, 7±2 wt.-% or 9±2 wt.-%, based on the totalweight of the pharmaceutical dosage form. In another preferredembodiment, the content of pharmacologically active compound is withinthe range of from 11±10 wt.-%, more preferably 11±9 wt.-%, still morepreferably 9±6 wt.-%, 11±6 wt.-%, 13±6 wt.-% or 15±6 wt.-%, mostpreferably 11±4 wt.-%, 13±4 wt.-% or 15±4 wt.-%, and in particular 11±2wt.-%, 13±2 wt.-% or 15±2 wt.-%, based on the total weight of thepharmaceutical dosage form. In a further preferred embodiment, thecontent of pharmacologically active compound is within the range of from20±6 wt.-%, more preferably 20±5 wt.-%, still more preferably 20±4wt.-%, most preferably 20±3 wt.-%, and in particular 20±2 wt.-%, basedon the total weight of the pharmaceutical dosage form.

Preferably, the total amount of the pharmacologically active compoundthat is contained in the pharmaceutical dosage form is within the rangeof from 0.01 to 200 mg, more preferably 0.1 to 190 mg, still morepreferably 1.0 to 180 mg, yet more preferably 1.5 to 160 mg, mostpreferably 2.0 to 100 mg and in particular 2.5 to 80 mg.

In a preferred embodiment, the pharmacologically active compound iscontained in the pharmaceutical dosage form in an amount of 7.5±5 mg,10±5 mg, 20±5 mg, 30±5 mg, 40±5 mg, 50±5 mg, 60±5 mg, 70±5 mg, 80±5 mg,90±5 mg, 100±5 mg, 110±5 mg, 120±5 mg, 130±5, 140±5 mg, 150±5 mg, or160±5 mg. In another preferred embodiment, the pharmacologically activecompound is contained in the pharmaceutical dosage form in an amount of5±2.5 mg, 7.5±2.5 mg, 10±2.5 mg, 15±2.5 mg, 20±2.5 mg, 25±2.5 mg, 30±2.5mg, 35±2.5 mg, 40±2.5 mg, 45±2.5 mg, 50±2.5 mg, 55±2.5 mg, 60±2.5 mg,65±2.5 mg, 70±2.5 mg, 75±2.5 mg, 80±2.5 mg, 85±2.5 mg, 90±2.5 mg, 95±2.5mg, 100±2.5 mg, 105±2.5 mg, 110±2.5 mg, 115±2.5 mg, 120±2.5 mg, 125±2.5mg, 130±2.5 mg, 135±2.5 mg, 140±2.5 mg, 145±2.5 mg, 150±2.5 mg, 155±2.5mg, or 160±2.5 mg.

In a preferred embodiment, the pharmacologically active compound isoxymorphone, preferably its hydrochloride salt, and the pharmaceuticaldosage form is adapted for administration twice daily. In thisembodiment, the pharmacologically active compound is preferablycontained in the pharmaceutical dosage form in an amount of from 5 to 40mg. In another particularly preferred embodiment, the pharmacologicallyactive compound is oxymorphone, preferably its hydrochloride salt, andthe pharmaceutical dosage form is adapted for administration once daily.In this embodiment, the pharmacologically active compound is preferablycontained in the pharmaceutical dosage form in an amount of from 10 to80 mg.

In another preferred embodiment, the pharmacologically active compoundis oxycodone, preferably its hydrochloride salt, and the pharmaceuticaldosage form is adapted for administration twice daily. In thisembodiment, the pharmacologically active compound is preferablycontained in the pharmaceutical dosage form in an amount of from 5 to 80mg, preferably 5 mg, 10 mg, 20 mg or 40 mg. In another particularlypreferred embodiment, the pharmacologically active compound isoxycodone, preferably its hydrochloride salt, and the pharmaceuticaldosage form is adapted for administration once daily. In thisembodiment, the pharmacologically active compound is preferablycontained in the pharmaceutical dosage form in an amount of from 10 to320 mg.

In still another particularly preferred embodiment, thepharmacologically active compound is hydromorphone, preferably itshydrochloride, and the pharmaceutical dosage form is adapted foradministration twice daily. In this embodiment, the pharmacologicallyactive compound is preferably contained in the pharmaceutical dosageform in an amount of from 2 to 52 mg. In another particularly preferredembodiment, the pharmacologically active compound is hydromorphone,preferably its hydrochloride salt, and the pharmaceutical dosage form isadapted for administration once daily. In this embodiment, thepharmacologically active compound is preferably contained in thepharmaceutical dosage form in an amount of from 4 to 104 mg.

In yet another particularly preferred embodiment, the pharmacologicallyactive compound is tapentadol, preferably its hydrochloride, and thepharmaceutical dosage form is adapted for administration twice daily. Inthis embodiment, the pharmacologically active compound is preferablycontained in the pharmaceutical dosage form in an amount of from 25 to250 mg. In another particularly preferred embodiment, thepharmacologically active compound is tapentadol, preferably itshydrochloride salt, and the pharmaceutical dosage form is adapted foradministration once daily. In this embodiment, the pharmacologicallyactive compound is preferably contained in the pharmaceutical dosageform in an amount of from 50 to 600 mg.

The pharmaceutical dosage form according to the invention furthercomprises an anionic polymer bearing carboxylic groups, wherein thecontent of the anionic polymer is 20 wt.-%, based on the total weight ofthe pharmaceutical dosage form.

Preferably, the anionic polymer comprises anionic functional groupsselected from carboxyl groups, sulfonyl groups, sulfate groups, andphosphoryl groups.

Preferably, the anionic polymer is derived from an ethylenicallyunsaturated monomer selected from (alk)acrylic acids, (alk)acrylicanhydrides, alkyl (alk)acrylates, or a combination thereof; i.e. theanionic polymer is preferably obtainable by polymerization of a monomercomposition comprising one or more of said ethylenically unsaturatedmonomers and optionally at least partial hydrolysis of the optionallypresent acid anhydride and/or carboxylic ester groups.

Preferably, the anionic polymer is obtainable by polymerization of amonomer composition comprising an ethylenically unsaturated monomerselected from ethylenically unsaturated carboxylic acids, ethylenicallyunsaturated carboxylic acid anhydrides, ethylenically unsaturatedsulfonic acids, and mixtures thereof.

Preferred ethylenically unsaturated carboxylic acid and ethylenicallyunsaturated carboxylic acid anhydride monomers include the acrylic acidstypified by acrylic acid itself, methacrylic acid, ethacrylic acid,alpha-chloracrylic acid, alpha-cyano acrylic acid, beta-methyl-acrylicacid (crotonic acid), alpha-phenyl acrylic acid, beta-acryloxy propionicacid, sorbic acid, alpha-chloro sorbic acid, angelic acid, cinnamicacid, p-chloro cinnamic acid, beta-styryl acrylic acid(1-carboxy-4-phenyl butadiene-1,3), itaconic acid, citraconic acid,mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaricacid, tricarboxy ethylene and maleic acid anhydride.

Preferred ethylenically unsaturated sulfonic acids include aliphatic oraromatic vinyl sulfonic acids such as vinylsulfonic acid, allyl sulfonicacid, vinyltoluenesulfonic acid and styrene sulfonic acid; acrylic andmethacrylic sulfonic acid such as sulfoethyl acrylate, sulfoethylmethacrylate, sulfopropyl acrylate, sulfopropyl methacrylate,2-hydroxy-3-acryloxy propyl sulfonic acid, 2-hydroxy-3-methacryloxypropyl sulfonic acid and 2-acrylamido-2-methyl propane sulfonic acid.

Preferably, the monomer composition comprises acrylic acid, methacrylicacid, and/or 2-acrylamido-2-methyl propane sulfonic acid. Acrylic acidis especially preferred.

For the purpose of the specification, the wording “obtainable bypolymerization of a monomer composition” does not necessarily requirethat the anionic polymer has been obtained from such a monomercomposition indeed. In other words, the anionic polymer is a polymercomprising at least one repeating unit which results from polymerizationof an ethylenically unsaturated monomer bearing an anionic functionalgroup, in protonated form or a physiologically acceptable salt thereof.

The anionic polymer may be linear or branched or cross-linked.

Preferably, the anionic polymer is hydrophilic, more preferablywater-soluble or water-swellable.

The anionic polymer may be a homopolymer or a copolymer. When theanionic polymer is a homopolymer, it comprises a single type ofrepeating unit, i.e. it is the polymerization product of a monomercomposition comprising a single type of monomer. When the anionicpolymer is a copolymer, it may comprise two, three or more differentrepeating units, i.e. may be the polymerization product of a monomercomposition comprising two, three or more different monomers.

In a preferred embodiment, the anionic polymer is a copolymer,comprising from about 50 mol-% to 99.999 mol-%, and more preferably fromabout 75 mol-% to 99.99 mol-% repeating units bearing anionic functionalgroups, preferably acid groups, more preferably carboxylic groups.

Preferably, the anionic polymer has an average equivalent weight of76±50 g/mol, more preferably of 76±30 g/mol, still more preferably of76±20 g/mol and most preferably of 76±10 g/mol per carboxyl group.

In a preferred embodiment, the monomer composition from which theanionic polymer is derivable further comprises a cross-linking agent,i.e. in this embodiment the anionic polymer is cross-linked.

Suitable cross-linking agents include

-   -   compounds having at least two polymerizable double bonds, e.g.        ethylenically unsaturated functional groups;    -   compounds having at least one polymerizable double bond, e.g. an        ethylenically unsaturated functional group, and at least one        functional group that is capable of reacting with another        functional group of one or more of the repeating units of the        anionic polymer;    -   compounds having at least two functional groups that are capable        of reacting with other functional groups of one or more of the        repeating units of the anionic polymer; and    -   polyvalent metal compounds which can form ionic cross-linkages,        e.g. through the anionic functional groups.

Cross-linking agents having at least two polymerizable double bonds,preferably allyl groups, are particularly preferred.

Cross-linking agents having at least two polymerizable double bondsinclude (i) di- or polyvinyl compounds such as divinylbenzene anddivinyltoluene; (ii) di- or poly-esters of unsaturated mono- orpoly-carboxylic acids with polyols including, for example, di- ortriacrylic acid esters of polyols such as ethylene glycol, trimethylolpropane, glycerine, or polyoxyethylene glycols; (iii) bisacrylamidessuch as N,N-methylenebisacrylamide; (iv) carbamyl esters that can beobtained by reacting polyisocyanates with hydroxyl group-containingmonomers; (v) di- or poly-allyl ethers of polyols; (vi) di- orpoly-allyl esters of polycarboxylic acids such as diallyl phthalate,diallyl adipate, and the like; (vii) esters of unsaturated mono- orpoly-carboxylic acids with mono-allyl esters of polyols such as acrylicacid ester of polyethylene glycol monoallyl ether; and (viii) di- ortriallyl amine.

In a preferred embodiment, divinyl glycol (1,5-hexadiene-3,4-diol) iscontained as cross-linking agent, whereas allyl or vinyl derivatives ofpolyols, such as allylsucrose or allyl pentaerythritol, are lesspreferred. This embodiment is preferably realized by polyacrylic acidpolymers of polycarbophil type according to USP.

In another preferred embodiment, allyl derivatives of polyols, such asallylsucrose or allyl pentaerythritol, are contained as cross-linkingagent, whereas divinyl glycol (1,5-hexadiene-3,4-diol) is lesspreferred. This embodiment is preferably realized by polyacrylic acidpolymers of carbomer type according to USP or Ph. Eur.

Cross-linking agents having at least one polymerizable double bond andat least one functional group capable of reacting with other functionalgroups of one or more of the repeating units of the anionic polymerinclude N-methylol acrylamide, glycidyl acrylate, and the like.

Suitable cross-linking agents having at least two functional groupscapable of reacting with other functional groups of one or more of therepeating units of the anionic polymer include glyoxal; polyols such asethylene glycol; polyamines such as alkylene diamines (e.g., ethylenediamine), polyalkylene polyamines, polyepoxides, di- or polyglycidylethers and the like.

Suitable polyvalent metal cross-linking agents which can form ioniccross-linkages include oxides, hydroxides and weak acid salts (e.g.,carbonate, acetate and the like) of alkaline earth metals (e.g., calciummagnesium) and zinc, including, for example, calcium oxide and zincdiacetate.

Of all of these types of cross-linking agents, the most preferred foruse herein are diol derivatives and polyol derivatives, morespecifically those selected from the group consisting of allyl sucrose,allyl pentaerythritol, divinyl glycol, divinyl polyethylene glycol and(meth)acrylic acid esters of diols.

In a preferred embodiment, the monomer composition from which theanionic polymer is derivable comprises the cross-linking agent in anamount of at most 1.0 mol-%, more preferably at most 0.1 mol-%, evenmore preferably at most about 0.01 mol-%, and most preferably at most0.005 mol-% based on all monomers forming the anionic polymer.

In a preferred embodiment, the anionic polymer is a homopolymer ofacrylic acid, optionally cross-linked, preferably with allyl sucrose orallyl pentaerythritol, in particular with allyl pentaerythritol. Inanother preferred embodiment, the anionic polymer is a copolymer ofacrylic acid and C₁₀-C₃₀-alkyl acrylate, optionally cross-linked,preferably with allyl pentaerythritol. In another preferred embodiment,the anionic polymer is a so-called interpolymer, namely a homopolymer ofacrylic acid, optionally cross-linked, preferably with allyl sucrose orallyl pentaerythritol; or a copolymer of acrylic acid and C₁₀-C₃₀-alkylacrylate, optionally cross-linked, preferably with allylpentaerythritol; which contain a block copolymer of polyethylene glycoland a long chain alkyl acid, preferably a C₈-C₃₀-alkyl acid. Polymers ofthis type are commercially available, e.g. under the trademarkCarbopol®.

When the anionic polymer is an interpolymer, it preferably exhibits aviscosity within the range of from 2,000 to 60,000 mPa·s, morepreferably 2,500 to 40,000 mPa·s, still more preferably 3,000 to 15,000mPa·s, measured by means of a Brookfield viscosimeter (RVF, 20 rpm,spindle 5) in a 0.5 wt.-% aqueous solution at pH 7.5 and 25° C.

Preferably, at least some of the anionic functional groups contained inthe anionic polymer are present in neutralized form, i.e. they are notpresent in their protonated forms, but are salts with salt-formingcations instead. Suitable salt-forming cations include alkali metal,ammonium, substituted ammonium and amines. More preferably, at leastsome of the anionic functional groups, e.g. carboxylate and/or sulfonateanions, are salts of sodium or potassium cations.

This percentage of neutralized anionic functional groups, i.e. thepercentage of anionic functional groups being present in neutralizedform, based on the total amount of anionic functional groups, isreferred to herein as the “degree of neutralization.” In a preferredembodiment, the degree of neutralization is within the range of from2.5±2.4%, more preferably 2.5±2.0%, still more preferably 2.5±1.5%, yetmore preferably 2.5±1.0%, and most preferably 2.5±0.5%. In anotherpreferred embodiment, the degree of neutralization is within the rangeof 35±30%, more preferably 35±25%, still more preferably 35±20%, yetmore preferably 35±15%, most preferably 35±10%, and in particular 35±5%.In yet another preferred embodiment, the degree of neutralization is inthe range of 65±30%, more preferably 65±25%, still more preferably65±20%, yet more preferably 65±15%, most preferably 65±10%, and inparticular 65±5%.

In a preferred embodiment, the anionic polymer has a weight averagemolecular weight (M_(W)) of at least 100,000 g/mol, preferably at least200,000 g/mol or at least 400,000 g/mol, more preferably in the range ofabout 500,000 g/mol to about 5,000,000 g/mol, and most preferably in therange of about 600,000 g/mol to about 2,000,000 g/mol. Suitable methodsto determine M_(W) are known to a person skilled in the art. Forinstance, M_(W) can be determined by gel permeation chromatography(GPC).

In a preferred embodiment, the pK_(A) of the anionic polymer is 6.0±2.0,more preferably 6.0±1.5, even more preferably 6.0±1.0, and mostpreferably 6.0±0.5. In another preferred embodiment, the pK_(A) of theanionic polymer is 7.0±2.0, more preferably 7.0±1.5, even morepreferably 7.0±1.0, and most preferably 7.0±0.5. In still anotherpreferred embodiment, the pK_(A) of the anionic polymer is 8.0±2.0, morepreferably 8.0±1.5, even more preferably 8.0±1.0, and most preferably8.0±0.5.

In a preferred embodiment, the pH (in 1 wt % aqueous dispersion) of theanionic polymer is 3.0±3.0, more preferably 3.0±2.0, even morepreferably 3.0±1.5, and most preferably 3.0±1.0.

In another preferred embodiment, the pH (in 1 wt % aqueous dispersion)of the anionic polymer is 6.0±3.0, more preferably 6.0±2.0, even morepreferably 6.0±1.5, and most preferably 6.0±1.0.

The anionic polymer preferably exhibits a viscosity of 2,000 to 100,000mPa s (cp), more preferably 3,000 to 80,000 mPa s, still more preferably4,000 to 60,000 mPa s, measured by means of a Brookfield viscometer(RVF, 20 rpm, spindle 5) in a 0.5 wt.-% aqueous solution at pH 7.5 and25° C.

In a preferred embodiment, the anionic polymer exhibits a viscosity ofat most 30,000 mPa s (cp), preferably at most 28,000 mPa s, morepreferably at most 25,000 mPa s, still more preferably at most 20,000mPa s or at most 15,000 mPa s, measured by means of a Brookfieldviscometer (RVF, 20 rpm, spindle 5) in a 0.5 wt.-% aqueous solution atpH 7.5 and 25° C.

Preferably, the overall content of anionic polymer is within the rangeof from 20 to 95 wt.-%, more preferably 20 to 90 wt.-%, most preferably25 to 75 wt.-%, and in particular 25 to 50 wt.-%, based on the totalweight of the pharmaceutical dosage form.

In a preferred embodiment, the overall content of anionic polymer is atleast 21 wt.-%, more preferably at least 22 wt.-%, still more preferablyat least 23 wt.-% or at least 24 wt.-%, most preferably at least 26wt.-% or 28 wt.-%, and in particular at least 30 wt.-% or at least 32wt.-%, based on the total weight of the pharmaceutical dosage form.

In a preferred embodiment, the overall content of anionic polymer iswithin the range of 20 to 50 wt.-%, more preferably 20 to 45 wt.-%,still more preferably 20 to 40 wt.-%, most preferably 20 to 35 wt.-%,and in particular preferably 20 to 30 wt.-%. In another preferredembodiment, the overall content of anionic polymer is within the rangeof 20 to 50 wt.-%, more preferably 20 to 45 wt.-%, still more preferably20 to 40 wt.-%, most preferably 20 to 35 or 25 to 40 wt.-%, and inparticular preferably 25 to 35 wt.-%. In still another preferredembodiment, the overall content of anionic polymer is within the rangeof 35±15 wt.-%, more preferably 35±10 wt.-%, and most preferably 35±5wt.-%. In yet another preferred embodiment, the overall content ofanionic polymer is within the range of 40±20 wt.-%, more preferably40±15 wt.-%, most preferably 40±10 wt.-%, and in particular 40±5 wt.-%.In a further preferred embodiment, the overall content of anionicpolymer is within the range of 50±20 wt.-%, more preferably 50±15 wt.-%,most preferably 50±10 wt.-%, and in particular 50±5 wt.-%.

Preferably, the relative weight ratio of the anionic polymer to thepharmacologically active compound is at least 0.5:1, more preferably atleast 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, atleast 6:1, at least 7:1, at least 8:1 or at least 9:1. In a preferredembodiment, the relative weight ratio of the anionic polymer to thepharmacologically active compound is within the range of from 5:1 to1:1, more preferably 4:1 to 2:1.

In a preferred embodiment, the relative weight ratio of thepharmacologically active ingredient to the anionic polymer is at most4.5:1, more preferably at most 4.0:1, still more preferably at most3.5:1, yet more preferably at most 3.0:1, even more preferably at most2.5:1, most preferably at most 2.0:1 and in particular at most 1.5:1. Ina particularly preferred embodiment, the relative weight ratio of thepharmacologically active ingredient to the anionic polymer is at most1.4:1, more preferably at most 1.3:1, still more preferably at most1.2:1, yet more preferably at most 1.1:1, even more preferably at most1.0:1, most preferably at most 0.9:1 and in particular at most 0.8:1.

Preferably, the relative weight ratio of the pharmacologically activeingredient to the sum of anionic polymer and nonionic surfactant is atmost 3.0:1, more preferably at most 2.8:1, still more preferably at most2.6:1, yet more preferably at most 2.4:1, even more preferably at most2.2:1, most preferably at most 2.0:1 and in particular at most 1.8:1. Ina particularly preferred embodiment, the relative weight ratio of thepharmacologically active ingredient to the sum of anionic polymer andnonionic surfactant is at most 1.6:1, more preferably at most 1.4:1,still more preferably at most 1.2:1, yet more preferably at most 1.0:1,even more preferably at most 0.8:1, most preferably at most 0.6:1 and inparticular at most 0.4:1.

In a preferred embodiment, the anionic polymer is homogeneouslydistributed in the pharmaceutical dosage form according to theinvention. Preferably, the anionic polymer forms a matrix in which thepharmacologically active compound is embedded. In a particularlypreferred embodiment, the pharmacologically active compound and theanionic polymer are intimately homogeneously distributed in thepharmaceutical dosage form so that the pharmaceutical dosage form doesnot contain any segments where either pharmacologically active compoundis present in the absence of anionic polymer, or where anionic polymeris present in the absence of pharmacologically active compound.

When the pharmaceutical dosage form is film coated, the anionic polymeris preferably homogeneously distributed in the core of thepharmaceutical dosage form, i.e. the film coating preferably does notcontain anionic polymer. Nonetheless, the film coating as such may ofcourse contain one or more polymers, which however, preferably differfrom the anionic polymer contained in the core.

The pharmaceutical dosage form according to the invention may eithercontain only one, or two or more anionic polymers of various types.

The anionic polymer may be combined with one or more different polymersselected from the group consisting of polyalkylene oxide, preferablypolymethylene oxide, polyethylene oxide, polypropylene oxide;polyethylene, polypropylene, polyvinyl chloride, polycarbonate,polystyrene, polyvinylpyrrolidone, poly(hydroxy fatty acids), such asfor example poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®),poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol,polyesteramide, polyethylene succinate, polylactone, polyglycolide,polyurethane, polyamide, polylactide, polyacetal (for examplepolysaccharides optionally with modified side chains),polylactide/glycolide, polylactone, polyglycolide, polyorthoester,polyanhydride, block polymers of polyethylene glycol and polybutyleneterephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymersthereof, block-copolymers thereof, or with mixtures of at least two ofthe stated polymers.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention does not contain any polyalkylene oxide having an averagemolecular weight of at least 200,000 g/mol, preferably at least 150,000g/mol, more preferably at least 100,000 g/mol, still more preferably atleast 75,000 g/mol, yet more preferably at least 50,000 g/mol, and mostpreferably at least 25,000 g/mol.

If, however, the anionic polymer is combined with one or more polymersselected from the group consisting of polyalkylene oxides, preferablypolymethylene oxide, polyethylene oxide and polypropylene oxide; thetotal content of polyalkylene oxide(s) having an average molecularweight of at least 200,000 g/mol is preferably 35 wt.-%, based on thetotal weight of the pharmaceutical dosage form.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains at least one polyalkylene oxide having an averagemolecular weight of at least 200,000 g/mol, preferably at least 150,000g/mol, more preferably at least 100,000 g/mol, still more preferably atleast 75,000 g/mol, yet more preferably at least 50,000 g/mol, and mostpreferably at least 25,000 g/mol. In this embodiment, the total contentof polyalkylene oxide(s) contained in the dosage form and having saidminimum average molecular weight is preferably ≦35 wt.-%, morepreferably ≦30 wt.-%, still more preferably ≦25 wt.-%, yet morepreferably ≦20 wt.-%, even more preferably ≦15 wt.-%, most preferably≦10 wt.-%, and in particular <5 wt.-%, based on the total weight of thepharmaceutical dosage form.

For the purpose of the specification, a polyalkylene oxide may comprisea single polyalkylene oxide having a particular average molecularweight, or a mixture (blend) of different polymers, such as two, three,four or five polymers, e.g., polymers of the same chemical nature butdifferent average molecular weight, polymers of different chemicalnature but same average molecular weight, or polymers of differentchemical nature as well as different molecular weight.

For the purpose of the specification, a polyalkylene glycol has amolecular weight of up to 20,000 g/mol whereas a polyalkylene oxide hasa molecular weight of more than 20,000 g/mol. Polyalkylene glycols, ifany, are preferably not taken into consideration when determining theweight average molecular weight of polyalkylene oxide.

In a preferred embodiment according to the invention, the anionicpolymer is combined with at least one further polymer, preferablyselected from the group consisting of polyethylene, polypropylene,polyvinyl chloride, polycarbonate, polystyrene, poly(hydroxy fattyacids), polycaprolactone, polyvinyl alcohol, polyesteramide,polyethylene succinate, polylactone, polyglycolide, polyurethane,polyvinylpyrrolidone, polyamide, polylactide, polylactide/glycolide,polylactone, polyglycolide, polyorthoester, polyanhydride, blockpolymers of polyethylene glycol and polybutylene terephthalate,polyanhydride, polyacetal, cellulose esters, cellulose ethers andcopolymers thereof. Cellulose esters and cellulose ethers areparticularly preferred, e.g. methylcellulose, ethylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulosehydroxypropylmethylcellulose, carboxymethylcellulose, and the like.

In a preferred embodiment, said further polymer is neither an anionicpolymer nor a polyalkylene glycol or polyalkylene oxide. Nonetheless,the pharmaceutical dosage form may contain polyalkylene glycol, e.g. asplasticizer, or a polyalkylene oxide, but then, the pharmaceuticaldosage form preferably is an at least ternary mixture of polymers:anionic polymer+further polymer+plasticizer or anionic polymer+furtherpolymer+polyalkylene oxide. A ternary mixture of anionic polymer+furtherpolymer+plasticizer is particularly preferred.

In a particularly preferred embodiment, said further polymer is ahydrophilic cellulose ester or cellulose ether, preferablyhydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) orhydroxyethylcellulose (HEC), preferably having an average viscosity(preferably measured by capillary viscosimetry or rotationalviscosimetry) of 1,000 to 150,000 mPas, more preferably 3,000 to150,000. In a preferred embodiment, the average viscosity is within therange of 110,000±50,000 mPas, more preferably 110,000±40,000 mPas, stillmore preferably 110,000±30,000 mPas, most preferably 110,000±20,000mPas, and in particular 100,000±10,000 mPas.

In a preferred embodiment, the further polymer is a cellulose ester orcellulose ether, preferably HPMC, having a content within the range of10±8 wt.-%, more preferably 10±6 wt.-%, still more preferably 10±5wt.-%, yet more preferably 10±4 wt.-%, most preferably 10±3 wt.-%, andin particular 10±2 wt.-%, based on the total weight of thepharmaceutical dosage form.

In another preferred embodiment, the further polymer is a celluloseester or cellulose ether, preferably HPMC, having a content within therange of 15±8 wt.-%, more preferably 15±6 wt.-%, still more preferably15±5 wt.-%, yet more preferably 15±4 wt.-%, most preferably 15±3 wt.-%,and in particular 15±2 wt.-%, based on the total weight of thepharmaceutical dosage form.

Preferably, the relative weight ratio of the sum of anionic polymer andnonionic surfactant to further polymer is within the range of from 1:1to 10:1, more preferably from 2:1 to 8:1.

In a preferred embodiment, the relative weight ratio of the sum ofanionic polymer and nonionic surfactant to further polymer is at least2.0:1, more preferably at least 2.5:1, still more preferably at least3.0:1, yet more preferably at least 3.5:1, even more preferably at least4.0:1, most preferably at least 4.5:1, and in particular at least 5.0:1.

The pharmaceutical dosage form according to the invention furthercomprises a nonionic surfactant.

In a preferred embodiment, the nonionic surfactant has ahydrophilic-lipophilic balance (HLB) of at least 10, preferably at least12, more preferably at least 14, still more preferably at least 16, yetmore preferably at least 18, even more preferably at least 20, mostpreferably at least 22, and in particular at least or more than 24.

The hydrophilic-lipophilic balance (HLB value) can be estimatedaccording to Griffin's method (Griffin, W. C.; J. Soc. Cosmet. Chem. 1(1949) 311).

Preferably, however, the HLB value is calculated by the incrementalmethod, i.e. by adding the individual HLB increments of all hydrophobicand hydrophilic groups present in the molecule. HLB increments of manyhydrophobic and hydrophilic groups can be found, e.g., in Fiedler, H.P., Encyclopedia of Excipients, Editio Cantor Verlag, Aulendorf, 6thEdition, 2007. The HLB value can further be determined experimentally,e.g. by partition chromatography or HPLC.

In another preferred embodiment, the nonionic surfactant exhibits asurface tension in 0.1% aqueous solution at 25° C. of at least 35dynes/cm, more preferably at least 40 dynes/cm, still more preferably atleast 43 dynes/cm, yet more preferably at least 45 dynes/cm, even morepreferably at least 47 dynes/cm, in particular at least 50 dynes/cm.

In another preferred embodiment, the nonionic surfactant exhibits aviscosity of at most 4000 mPa·s, more preferably at most 3500 mPa·s,still more preferably at most 3000 mPa·s, yet more preferably at most2500 mPa·s, even more preferably at most 2000 mPa·s, most preferably atmost 1500 mPa·s, and in particular at most 1000 mPa·s, measured at 70°C. using a model LVF or LVT Brookfield viscosimeter.

Suitable non-ionic surfactants include but are not limited to

-   -   polyoxypropylene-polyoxyethylene block copolymers (e.g.,        poloxamers or poloxamines), preferably according to general        formula (I-a)

-   -   wherein a and c are each independently an integer of from 5 to        250, and b is an integer of from 10 to 100; preferably, a=c≠b;        and/or a=c>b;    -   or according to general formula (I-b)

-   -   wherein e, f, g and h are each independently an integer of from        1 to 150, and i, j, k and l are each independently an integer of        from 2 to 50; and preferably, the ratio (e+f+g+h)/(i+j+k+l) is        an integer of from 0.015 to 30;    -   fatty alcohols that may be linear or branched, such as        cetylalcohol, stearylalcohol, cetylstearyl alcohol,        2-octyldodecane-1-ol and 2-hexyldecane-1-ol;    -   sterols, such as cholesterole;    -   partial fatty acid esters of sorbitan such as        sorbitanmonolaurate, sorbitanmonopalmitate,        sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate,        sorbitansesquioleate and sorbitantrioleate;    -   partial fatty acid esters of polyoxyethylene sorbitan        (polyoxyethylene-sorbitan-fatty acid esters), preferably a fatty        acid monoester of polyoxyethylene sorbitan, a fatty acid diester        of polyoxyethylene sorbitan, or a fatty acid triester of        polyoxyethylene sorbitan; e.g. mono- and tri-lauryl, palmityl,        stearyl and oleyl esters, such as the type known under the name        “polysorbat” and commercially available under the trade name        “Tween” including Tween® 20 [polyoxyethylene(20)sorbitan        monolaurate], Tween® 21 [polyoxyethylene(4)sorbitan        monolaurate], Tween® 40 [polyoxyethylene(20)sorbitan        monopalmitate], Tween® 60 [polyoxyethylene(20)sorbitan        monostearate], Tween® 65 [polyoxyethylene(20)sorbitan        tristearate], Tween® 80 [polyoxyethylene(20)sorbitan        monooleate], Tween 81 [polyoxyethylene(5)sorbitan monooleate],        and Tween® 85 [polyoxyethylene(20)sorbitan trioleate];        preferably a fatty acid monoester of polyoxyethylenesorbitan        according to general formula (I-c)

-   -   -   wherein (w+x+y+z) is within the range of from 15 to 100,            preferably 16 to 80, more preferably 17 to 60, still more            preferably 18 to 40 and most preferably 19 to 21; and            alkylene is an optionally unsaturated alkylene group            comprising 6 to 30 carbon atoms, more preferably 8 to 24            carbon atoms and most preferably 10 to 16 carbon atoms;

    -   polyoxyethyleneglycerole fatty acid esters such as mixtures of        mono-, di- and triesters of glycerol and di- and monoesters of        macrogols having molecular weights within the range of from 200        to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate,        macrogolglycerollaurate, macrogolglycerolococoate,        macrogolglycerollinoleate, macrogol-20-glycerolmonostearate,        macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate;        macrogolglycerolstearate, macrogolglycerolhydroxystearate (e.g.        Cremophor® RH 40), and macrogolglycerolrizinoleate (e.g.        Cremophor® EL);

    -   polyoxyethylene fatty acid esters, the fatty acid preferably        having from about 8 to about 18 carbon atoms, e.g.        macrogololeate, macrogolstearate, macrogol-15-hydroxystearate,        polyoxyethylene esters of 12-hydroxystearic acid, such as the        type known and commercially available under the trade name        “Solutol HS 15”; preferably according to general formula (I-d)

CH₃CH₂—(OCH₂CH₃)_(n)—O—CO—(CH₂)_(m)CH₃  (I-d)

-   -   -   wherein n is an integer of from 6 to 500, preferably 7 to            250, more preferably 8 to 100, still more preferably 9 to            75, yet more preferably 10 to 50, even more preferably 11 to            30, most preferably 12 to 25, and in particular 13 to 20;            and        -   wherein m is an integer of from 6 to 28; more preferably 6            to 26, still more preferably 8 to 24, yet more preferably 10            to 22, even more preferably 12 to 20, most preferably 14 to            18 and in particular 16;

    -   polyoxyethylene fatty alcohol ethers, e.g.        macrogolcetylstearylether, macrogollaurylether,        macrogololeylether, macrogolstearylether;

    -   fatty acid esters of saccharose; e.g. saccharose distearate,        saccharose dioleate, saccharose dipalmitate, saccharose        monostearate, saccharose monooleate, saccharose monopalmitate,        saccharose monomyristate and saccharose monolaurate;

    -   fatty acid esters of polyglycerol, e.g. polyglycerololeate;

    -   polyoxyethylene esters of alpha-tocopheryl succinate, e.g.        D-alpha-tocopheryl-PEG-1000-succinate (TPGS);

    -   polyglycolyzed glycerides, such as the types known and        commercially available under the trade names “Gelucire 44/14”,        “Gelucire 50/13 and “Labrasol”;

    -   reaction products of a natural or hydrogenated castor oil and        ethylene oxide such as the various liquid surfactants known and        commercially available under the trade name “Cremophor”; and

    -   partial fatty acid esters of multifunctional alcohols, such as        glycerol fatty acid esters, e.g. mono- and tri-lauryl, palmityl,        stearyl and oleyl esters, for example glycerol monostearate,        glycerol monooleate, e.g. glyceryl monooleate 40, known and        commercially available under the trade name “Peceol”; glycerole        dibehenate, glycerole distearate, glycerole monolinoleate;        ethyleneglycol monostearate, ethyleneglycol monopalmitostearate,        pentaerythritol monostearate.

In a preferred embodiment, the nonionic surfactant is a thermosensitivepolymer, in particular an inverse thermosensitive polymer, i.e. apolymer that is soluble in water at a comparatively low temperature,e.g. below or about 20° C., but gels (forms a gel) at highertemperatures, e.g. above 35° C.

For the purpose of the specification, an “inverse thermosensitivepolymer” preferably is a polymer exhibiting an atypical dependency ofviscosity from temperature; while aqueous dispersions of conventionalpolymers typically show decreased viscosities at increased temperatures,the viscosity of an aqueous dispersion of an inverse thermosensitivepolymer according to the invention increases at increased temperatures,at least within a certain temperature range above ambient temperature.Preferably, the increase of viscosity that is induced by an increase oftemperature leads to gel formation so that an aqueous dispersion of aninverse thermosensitive polymer according to the invention preferablyforms a liquid solution at ambient temperature but a viscous gel atelevated temperature. Polymeric nonionic surfactants exhibiting theseproperties are known to the skilled artisan.

A skilled person recognizes that viscosity and gel strength may decreaseagain, once a certain temperature is exceeded. Thus, an aqueousdispersion of an inverse thermosensitive polymer according to theinvention preferably has a viscosity maximum, which at a concentrationof 25 wt.-%, relative to the total weight of the aqueous dispersion, ispreferably within the range 45±20° C., or 55±20° C., or 65±20° C., or75±20° C.

Thus, the nonionic surfactant according to the invention preferablyforms a liquid solution in water at ambient temperature, and when thetemperature is increased, the surfactant forms an aqueous gel, at leastwithin a certain temperature range above ambient temperature.

Preferably, in pure water at a concentration of 25 wt.-% the nonionicsurfactant forms an aqueous dispersion having a viscosity η₁ at atemperature T₁ of 20° C. and a viscosity η₂ at a temperature T₂ of morethan 20° C. (i.e. T₂>T₁), where η₂>η₁. This does not necessarily meanthat viscosity η₂ at any temperature T₂ above 20° C. must be greaterthan viscosity η₁ at 20° C. Instead, this means that there is at leastone temperature T₂ above 20° C. at which viscosity η₂ of the aqueousdispersion is greater than viscosity η₁ at T₁ (=20° C.).

Preferably, an aqueous solution comprising at least 20 wt.-% or at least25 wt.-% nonionic surfactant shows a thermoreversible behavior, i.e. theviscosity of the solution increases with increasing temperature anddecreases with decreasing temperature, and repeated heating and coolingdoes not affect this property. Preferably, the aqueous solution exhibitsa thermoreversible behavior with a maximum viscosity between 30 and 80°C.

In an especially preferred embodiment, the aqueous solution is a liquidat 20° C. and forms a semi-solid gel upon heating to a temperature of atmost 80° C., more preferably 60° C., most preferably at most 45° C., andin particular at most 37° C.

Preferably, the sol-gel transition temperature, i.e. the temperature atwhich the phase transition occurs, is within the range of from 10° C. to80° C., more preferably within the range of from 15° C. to 75° C., andmost preferably within the range of from 20° C. to 60° C.

For example, various poloxamines and poloxamers, including poloxamer 407and poloxamer 188, show inverse thermosensitivity.

Particularly preferably, the nonionic surfactant is apolyoxypropylene-polyoxyethylene block copolymer, preferably selectedfrom poloxamers and poloxamines, in particularpolyoxypropylene-polyoxyethylene block copolymer according to generalformula (I-a) and polyoxypropylene-polyoxyethylene block copolymeraccording to general formula (I-b).

In a particular preferred embodiment, the nonionic surfactant is apolyoxypropylene-polyoxyethylene block copolymer according to generalformula (I-a)

wherein a and c are each independently an integer of from 5 to 250, andb is an integer of from 10 to 100; and preferably, a=c≠b; and/or a=c>b.More preferably, a and c are each independently an integer of from 10 to120, and b is an integer of from 15 to 75; and preferably, a=c>b.Polyoxypropylene-polyoxyethylene block copolymers of this type are alsoknown as poloxamers and are commercially available under the trade namePluronics.

In a preferred embodiment, a, b and c are each independently an integeras specified as preferred embodiments N¹ to N³² in the table here below:

a b c N¹  80 ± 75 27 ± 17  80 ± 75 N²  80 ± 65 27 ± 16  80 ± 65 N³  80 ±55 27 ± 15  80 ± 55 N⁴  80 ± 50 27 ± 14  80 ± 50 N⁵  80 ± 45 27 ± 13  80± 45 N⁶  80 ± 40 27 ± 12  80 ± 40 N⁷  80 ± 35 27 ± 11  80 ± 35 N⁸  80 ±31 27 ± 10  80 ± 31 N⁹  80 ± 27 27 ± 9  80 ± 27 N¹⁰  80 ± 23 27 ± 8  80± 23 N¹¹  80 ± 19 27 ± 7  80 ± 19 N¹²  80 ± 15 27 ± 6  80 ± 15 N¹³  80 ±12 27 ± 5  80 ± 12 N¹⁴  80 ± 9 27 ± 4  80 ± 9 N¹⁵  80 ± 6 27 ± 3  80 ± 6N¹⁶  80 ± 3 27 ± 2  80 ± 3 N¹⁷  12 ± 11 20 ± 15  12 ± 11 N¹⁸  12 ± 8 20± 12  12 ± 8 N¹⁹  12 ± 5 20 ± 8  12 ± 5 N²⁰  12 ± 2 20 ± 4  12 ± 2 N²¹ 64 ± 45 37 ± 13  64 ± 45 N²²  64 ± 20 37 ± 10  64 ± 20 N²³  64 ± 12 37± 7  64 ± 12 N²⁴  64 ± 5 37 ± 5  64 ± 5 N²⁵ 101 ± 80 56 ± 35 101 ± 80N²⁶ 101 ± 55 56 ± 21 101 ± 55 N²⁷ 101 ± 31 56 ± 12 101 ± 31 N²⁸ 101 ± 1556 ± 8 101 ± 15 N²⁹ 141 ± 120 44 ± 31 141 ± 120 N³⁰ 141 ± 90 44 ± 27 141± 90 N³¹ 141 ± 35 44 ± 19 141 ± 35 N³² 141 ± 17 44 ± 11 141 ± 17

In another preferred embodiment, the nonionic surfactant is apolyoxypropylene-polyoxyethylene block copolymer according to generalformula (I-b)

wherein e, f, g and h are each independently an integer of from 1 to150, and i, j, k and l are each independently an integer of from 2 to50; and preferably, the ratio (e+f+g+h)/(i+j+k+l) is from 0.015 to 30,in particular from 1 to 10. More preferably, e, f, g and h are eachindependently an integer of from 3 to 50, and i, j, k and l are eachindependently an integer of from 2 to 30. Tetrafunctionalpolyoxypropylene-polyoxyethylene block copolymers of this type are alsoknown as poloxamines and are commercially available under the trade nameTetronics.

Preferably, the nonionic surfactant, preferably according to generalformula (I-a) or according to general formula (I-b) has an averagemolecular weight of at least 2,000 g/mol, more preferably at least 3,000g/mol, still more preferably at least 4,000 g/mol, yet more preferablyat least 5,000 g/mol, even more preferably at least 6,000 g/mol, mostpreferably at least 7,000 g/mol, and in particular at least 7,500 g/mol.

In a preferred embodiment, the nonionic surfactant, preferably accordingto general formula (I-a) or according to general formula (I-b) has anaverage molecular weight of at most 30,000 g/mol, more preferably atmost 25,000 g/mol, still more preferably at most 20,000 g/mol, yet morepreferably at most 15,000 g/mol, even more preferably at most 12,500g/mol, most preferably at most 10,000 g/mol, and in particular at most9,500 g/mol.

Preferably, the nonionic surfactant, preferably according to generalformula (I-a) or according to general formula (I-b) has an averagemolecular weight as specified as preferred embodiments O¹ to O³² in thetable here below:

g/mol M_(w) O¹  8,600 ± 7,500 O²  8,600 ± 5,000 O³  8,600 ± 4,000 O⁴ 8,600 ± 3,000 O⁵  8,600 ± 2,500 O⁶  8,600 ± 2,250 O⁷  8,600 ± 2,000 O⁸ 8,600 ± 1,750 O⁹  8,600 ± 1,500 O¹⁰  8,600 ± 1,400 O¹¹  8,600 ± 1,300O¹²  8,600 ± 1,200 O¹³  8,600 ± 1,100 O¹⁴  8,600 ± 1,000 O¹⁵  8,600 ±950 O¹⁶  8,600 ± 920 O¹⁷  2,200 ± 1,000 O¹⁸  2,200 ± 500 O¹⁹  2,200 ±250 O²⁰  7,800 ± 6,000 O²¹  7,800 ± 4,000 O²²  7,800 ± 1,500 O²³  7,800± 1,000 O²⁴  7,800 ± 800 O²⁵ 12,200 ± 8,000 O²⁶ 12,200 ± 4,000 O²⁷12,200 ± 3,000 O²⁸ 12,200 ± 1,500 O²⁹ 15,000 ± 7,500 O³⁹ 15,000 ± 5,000O³¹ 15,000 ± 3,000 O³² 15,000 ± 2,000

Preferably, the nonionic surfactant, preferably according to generalformula (I-a) or according to general formula (I-b) has an oxyethylenecontent, as determined according to USP or Ph. Eur., of at least 60%,more preferably at least 70%, still more preferably at least 72%, yetmore preferably at least 74%, even more preferably at least 76%, mostpreferably at least 78%, and in particular at least 80%.

Preferably, the nonionic surfactant, preferably according to generalformula (I-a) or according to general formula (I-b) has an oxyethylenecontent, as determined according to USP or Ph. Eur., of at most 90%,more preferably at most 89%, still more preferably at most 88%, yet morepreferably at most 87%, even more preferably at most 86%, mostpreferably at most 85%, and in particular at most 84%.

Preferably, the nonionic surfactant, preferably according to generalformula (I-a) or according to general formula (I-b) has an oxyethylenecontent, as determined according to USP or Ph. Eur., as specified aspreferred embodiments P¹ to P³² in the table here below:

% OE-content % P¹ 81.8 ± 17.0 P² 81.8 ± 16.0 P³ 81.8 ± 15.0 P⁴ 81.8 ±14.0 P⁵ 81.8 ± 13.0 P⁶ 81.8 ± 12.0 P⁷ 81.8 ± 11.0 P⁸ 81.8 ± 10.0 P⁹ 81.8± 9.0 P¹⁰ 81.8 ± 8.0 P¹¹ 81.8 ± 7.0 P¹² 81.8 ± 6.0 P¹³ 81.8 ± 5.0 P¹⁴81.8 ± 4.0 P¹⁵ 81.8 ± 3.0 P¹⁶ 81.8 ± 2.0 P¹⁷ 46.5 ± 15.0 P¹⁸ 46.5 ± 10.0P¹⁹ 46.5 ± 5.0 P²⁰ 60.0 ± 20.0 P²¹ 60.0 ± 15.0 P²² 70.0 ± 10.0 P²³ 70.0± 8.0 P²⁴ 70.0 ± 5.0 P²⁵ 73.0 ± 6.0 P²⁶ 73.0 ± 4.0 P²⁷ 75.0 ± 5.0 P²⁸75.0 ± 4.0 P²⁹ 75.0 ± 3.0 P³⁰ 85.0 ± 5.0 P³¹ 85.0 ± 4.0 P³² 85.0 ± 3.0

The content of the nonionic surfactant in the pharmaceutical dosage formis not limited.

Preferably, the content of the nonionic surfactant in the pharmaceuticaldosage form according to the invention is such that liquid extraction ofthe pharmacologically active compound and thus, parenteraladministration of the liquid extract, is impeded.

Preferably, the content of the nonionic surfactant is at least 0.1wt.-%, more preferably at least 1.0 wt.-%, still more at least 5 wt.-%,yet more preferably at least 10 wt.-%, most preferably at least 15wt.-%, and in particular at least 20 wt.-%, based on the total weight ofthe pharmaceutical dosage form.

Preferably, the content of the nonionic surfactant is within the rangeof from 0.1 to 60 wt.-%, more preferably 5 to 50 wt.-%, still morepreferably 10 to 45 wt.-%, most preferably 15 to 40 wt.-%, and inparticular 20 to 35 wt.-%, based on the total weight of thepharmaceutical dosage form.

In a preferred embodiment, the content of nonionic surfactant is withinthe range of 15±12 wt.-%, more preferably 15±10 wt.-%, most preferably15±7 wt.-%, and in particular 15±5 wt.-%, based on the total weight ofthe pharmaceutical dosage form. In another preferred embodiment, thecontent of nonionic surfactant is within the range of 20±18 wt.-%, morepreferably 20±15 wt.-%, still more preferably 20±12 wt.-%, mostpreferably 20±10 wt.-%, 20±7 wt.-%, and in particular 20±5 wt.-%, basedon the total weight of the pharmaceutical dosage form. In a furtherpreferred embodiment, the content of nonionic surfactant is within therange of 25±20 wt.-%, more preferably 25±17 wt.-%, still more preferably25±15 wt.-%, even more preferably 25±10 wt.-%, most preferably 25±7wt.-%, and in particular 25±5 wt.-%, based on the total weight of thepharmaceutical dosage form.

In a preferred embodiment, the content of nonionic surfactant is withinthe range of 30±20 wt.-%, more preferably 30±17 wt.-%, still morepreferably 30±15 wt.-%, even more preferably 30±10 wt.-%, mostpreferably 30±7 wt.-%, and in particular 30±5 wt.-%, based on the totalweight of the pharmaceutical dosage form. In another further preferredembodiment, the content of nonionic surfactant is within the range of35±20 wt.-%, more preferably 35±17 wt.-%, still more preferably 35±15wt.-%, even more preferably 35±10 wt.-%, most preferably 35±7 wt.-%, andin particular 35±5 wt.-%, based on the total weight of thepharmaceutical dosage form. In a further preferred embodiment, thecontent of nonionic surfactant is within the range of 40±25 wt.-%, morepreferably 40±15 wt.-%, still more preferably 40±10 wt.-%, mostpreferably 40±7 wt.-%, and in particular 40±5 wt.-%, based on the totalweight of the pharmaceutical dosage form.

Preferably, the total amount of the nonionic surfactant that iscontained in the pharmaceutical dosage form is within the range of from0.1 to 750 mg, more preferably 10 to 500 mg, still more preferably 25 to400 mg, yet more preferably 50 to 350 mg, most preferably 75 to 300 mgand in particular 100 to 250 mg.

In a preferred embodiment, the nonionic surfactant is contained in thepharmaceutical dosage form in an amount of 100±95 mg, 100±90 mg, 100±80mg, 100±70 mg, 100±60 mg, 100±50 mg, 100±40 mg, 100±30 mg, 100±20 mg, or100±10 mg. In another preferred embodiment, the nonionic surfactant iscontained in the pharmaceutical dosage form in an amount of 120±115 mg,120±100 mg, 120±90 mg, 120±80 mg, 120±70 mg, 120±60 mg, 120±50 mg,120±40 mg, 120±30 mg, 120±20 mg, or 120±10 mg. In still anotherpreferred embodiment, the nonionic surfactant is contained in thepharmaceutical dosage form in an amount of 140±135 mg, 140±120 mg,140±110 mg, 140±100 mg, 140±90 mg, 140±80 mg, 140±70 mg, 140±60 mg,140±50 mg, 140±40 mg, 140±30 mg, 140±20 mg, or 140±10 mg. In yet anotherpreferred embodiment, the nonionic surfactant is contained in thepharmaceutical dosage form in an amount of 160±155 mg, 160±140 mg,160±130 mg, 160±120 mg, 160±110 mg, 160±100 mg, 160±90 mg, 160±80 mg,160±70 mg, 160±60 mg, 160±50 mg, 160±40 mg, 160±30 mg, 160±20 mg, or160±10 mg.

In a preferred embodiment, the nonionic surfactant is contained in thepharmaceutical dosage form in an amount of 180±175 mg, 180±160 mg,180±150 mg, 180±140 mg, 180±130 mg, 180±120 mg, 180±110 mg, 180±100 mg,180±90 mg, 180±80 mg, 180±70 mg, 180±60 mg, 180±50 mg, 180±40 mg, 180±30mg, 180±20 mg, or 180±10 mg. In another preferred embodiment, thenonionic surfactant is contained in the pharmaceutical dosage form in anamount of 200±190 mg, 200±180 mg, 200±170 mg, 200±160 mg, 200±150 mg,200±140 mg, 200±130 mg, 200±120 mg, 200±110 mg, 200±100 mg, 200±90 mg,200±80 mg, 200±70 mg, 200±60 mg, 200±50 mg, 200±40 mg, 200±30 mg, 200±20mg, or 200±10 mg. In still another preferred embodiment, the nonionicsurfactant is contained in the pharmaceutical dosage form in an amountof 220±210 mg, 220±200 mg, 220±180 mg, 220±160 mg, 220±150 mg, 220±140mg, 220±130 mg, 220±120 mg, 220±110 mg, 220±100 mg, 220±90 mg, 220±80mg, 220±70 mg, 220±60 mg, 220±50 mg, 220±40 mg, 220±30 mg, 220±20 mg, or220±10 mg. In yet another preferred embodiment, the nonionic surfactantis contained in the pharmaceutical dosage form in an amount of 240±210mg, 240±200 mg, 240±180 mg, 240±160 mg, 240±150 mg, 240±140 mg, 240±130mg, 240±120 mg, 240±110 mg, 240±100 mg, 240±90 mg, 240±80 mg, 240±70 mg,240±60 mg, 240±50 mg, 240±40 mg, 240±30 mg, 240±20 mg, or 240±10 mg.

Preferably, the relative weight ratio of the pharmacologically activecompound and the nonionic surfactant is within the range of from 20:1 to1:20, more preferably 15:1 to 1:15, still more preferably 10:1 to 1:10,yet more preferably 5:1 to 1:10, even more preferably 2:1 to 1:5, mostpreferably 1:1 to 1:4, and in particular 1:1.5 to 1:3.

In a preferred embodiment, the relative weight ratio of thepharmacologically active compound and the nonionic surfactant is at most6.5:1, more preferably at most 5.0:1, still more preferably at most4.0:1, yet more preferably at most 3.0:1, even more preferably at most2.5:1, most preferably at most 2.0:1, and in particular at most 1.5:1.In a particularly preferred embodiment, the relative weight ratio of thepharmacologically active compound and the nonionic surfactant is at most1.4:1, more preferably at most 1.3:1, still more preferably at most1.2:1, yet more preferably at most 1.1:1, even more preferably at most1.0:1, most preferably at most 0.9:1, and in particular at most 0.8:1.

Preferably, the relative weight ratio of the anionic polymer and thenonionic surfactant is within the range of from 20:1 to 1:20, morepreferably 15:1 to 1:15, still more preferably 10:1 to 1:10, yet morepreferably 5:1 to 1:5, even more preferably 5:1 to 1:3, most preferably3:1 to 1:2, and in particular 2:1 to 1:2.

In a preferred embodiment, the nonionic surfactant is homogeneouslydistributed in the pharmaceutical dosage form according to theinvention.

Preferably, the pharmacologically active compound, the anionic polymerand the nonionic surfactant are homogeneously distributed over thepharmaceutical dosage form or, when the pharmaceutical dosage formcomprises a film coating, over the coated core of the pharmaceuticaldosage form.

In a particularly preferred embodiment, the pharmacologically activecompound, the anionic polymer and the nonionic surfactant are intimatelymixed with one another, so that the pharmaceutical dosage form does notcontain any segments where either pharmacologically active compound ispresent in the absence of anionic polymer and/or the nonionicsurfactant, or where anionic polymer is present in the absence ofpharmacologically active compound and/or the surfactant.

Preferably, the pharmacologically active compound and the nonionicsurfactant are homogeneously dispersed in the anionic polymer,preferably in molecular disperse form or solid disperse form. In otherwords, the pharmacologically active compound and the nonionic surfactantpreferably form a solid solution or solid dispersion in the anionicpolymer.

Preferably, the pharmacologically active compound is embedded in aprolonged release matrix comprising the anionic polymer and the nonionicsurfactant. Thus, the prolonged release matrix is preferably ahydrophilic matrix. Preferably, the release profile of thepharmacologically active compound is matrix-retarded. Preferably, thepharmacologically active compound is embedded in a matrix comprising theanionic polymer and the nonionic surfactant, said matrix controlling therelease of the pharmacologically active compound from the pharmaceuticaldosage form.

Physiologically acceptable materials which are known to the personskilled in the art may be used as supplementary matrix materials.Polymers, particularly preferably cellulose ethers and/or celluloseesters are preferably used as supplementary hydrophilic matrixmaterials. Ethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,and/or the derivatives thereof, such as the salts thereof are veryparticularly preferably used as matrix materials.

Preferably, the pharmaceutical dosage form according to the invention isfor oral administration.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is configured for administration once daily, preferablyorally. In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is configured for administration twice daily,preferably orally. In still another preferred embodiment, thepharmaceutical dosage form according to the invention is configured foradministration thrice daily, preferably orally.

For the purpose of the specification, “twice daily” means equal ornearly equal time intervals, i.e., about every 12 hours, or differenttime intervals, e.g., 8 and 16 hours or 10 and 14 hours, between theindividual administrations.

For the purpose of the specification, “thrice daily” means equal ornearly equal time intervals, i.e., about every 8 hours, or differenttime intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, betweenthe individual administrations.

Preferably, the pharmaceutical dosage form according to the inventioncauses an at least partially delayed or prolonged release ofpharmacologically active compound.

Controlled or prolonged release is understood according to the inventionpreferably to mean a release profile in which the pharmacologicallyactive compound is released over a relatively long period with reducedintake frequency with the purpose of extended therapeutic action of thepharmacologically active compound. Preferably, the meaning of the term“prolonged release” is in accordance with the European guideline on thenomenclature of the release profile of pharmaceutical dosage forms(CHMP). This is achieved in particular with peroral administration. Theexpression “at least partially delayed or prolonged release” coversaccording to the invention any pharmaceutical dosage forms which ensuremodified release of the pharmacologically active compound containedtherein. The pharmaceutical dosage forms preferably comprise coated oruncoated pharmaceutical dosage forms, which are produced with specificauxiliary substances, by particular processes or by a combination of thetwo possible options in order purposefully to change the release rate orlocation of release.

In the case of the pharmaceutical dosage forms according to theinvention, the release profile of a controlled release form may bemodified e.g. as follows: extended release, repeat action release,prolonged release and sustained release.

For the purpose of the specification “controlled release” preferablymeans a product in which the release of active compound over time iscontrolled by the type and composition of the formulation. For thepurpose of the specification “extended release” preferably means aproduct in which the release of active compound is delayed for a finitelag time, after which release is unhindered. For the purpose of thespecification “repeat action release” preferably means a product inwhich a first portion of active compound is released initially, followedby at least one further portion of active compound being releasedsubsequently. For the purpose of the specification “prolonged release”preferably means a product in which the rate of release of activecompound from the formulation after administration has been reduced overtime, in order to maintain therapeutic activity, to reduce toxiceffects, or for some other therapeutic purpose. For the purpose of thespecification “sustained release” preferably means a way of formulatinga medicine so that it is released into the body steadily, over a longperiod of time, thus reducing the dosing frequency. For further details,reference may be made, for example, to K. H. Bauer, Lehrbuch derPharmazeutischen Technologie, 6th edition, WVG Stuttgart, 1999; and Eur.Ph.

The pharmaceutical dosage form according to the invention may compriseone or more pharmacologically active compounds at least in part in afurther controlled release form, wherein controlled release may beachieved with the assistance of conventional materials and processesknown to the person skilled in the art, for example by embedding thesubstances in a controlled release matrix or by applying one or morecontrolled release coatings. Substance release must, however, becontrolled such that addition of delayed-release materials does notimpair the necessary breaking strength. Controlled release from thepharmaceutical dosage form according to the invention is preferablyachieved by embedding the pharmacologically active compound in a matrix.Matrix materials may, for example, be hydrophilic, gel-formingmaterials, from which release proceeds mainly by erosion and diffusion.Preferably, the anionic polymer and the nonionic surfactant serve asmatrix material, optionally in combination with auxiliary substancesalso acting as matrix materials.

Preferably, the release profile is substantially matrix controlled,preferably by embedding the pharmacologically active compound in amatrix comprising the anionic polymer and optionally, further matrixmaterials, such as the nonionic surfactant and/or the optionally presentfurther polymer. Preferably, the release profile is not osmoticallydriven. Preferably, release kinetics is not zero order.

In preferred embodiments, in accordance with Ph. Eur., the in vitrorelease profile of the pharmacologically active compound complies withany same single one of the following release profiles R¹ to R⁵⁰:

% R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ R¹⁰  1 h 15 ± 14 15 ± 13 15 ± 12 15 ± 11 15± 10 15 ± 9 15 ± 8 15 ± 7 15 ± 6 15 ± 5  2 h 25 ± 20 25 ± 18 25 ± 17 25± 16 25 ± 15 25 ± 14 25 ± 13 25 ± 12 25 ± 11 25 ± 10  8 h 55 ± 35 55 ±32 55 ± 29 55 ± 27 55 ± 25 55 ± 23 55 ± 21 55 ± 19 55 ± 17 55 ± 15 12 h70 ± 35 70 ± 32 70 ± 29 70 ± 27 70 ± 25 70 ± 23 70 ± 21 70 ± 19 70 ± 1770 ± 15 24 h ≧65 ≧70 ≧70 ≧70 ≧75 ≧75 ≧75 ≧80 ≧80 ≧80 % R¹¹ R¹² R¹³ R¹⁴R¹⁵ R¹⁶ R¹⁷ R¹⁸ R¹⁹ R²⁰  1 h 20 ± 18 20 ± 16 20 ± 14 20 ± 12 20 ± 10 20± 9 20 ± 8 20 ± 7 20 ± 6 20 ± 5  2 h 30 ± 28 30 ± 26 30 ± 24 30 ± 22 30± 20 30 ± 18 30 ± 16 30 ± 14 30 ± 12 30 ± 10  8 h 60 ± 35 60 ± 32 60 ±29 60 ± 27 60 ± 25 60 ± 23 60 ± 21 60 ± 19 60 ± 17 60 ± 15 12 h 75 ± 3575 ± 32 75 ± 29 75 ± 27 75 ± 30 75 ± 23 75 ± 21 75 ± 19 75 ± 17 75 ± 1524 h ≧75 ≧77 ≧79 ≧81 ≧83 ≧85 ≧87 ≧89 ≧90 ≧90 % R²¹ R²² R²³ R²⁴ R²⁵ R²⁶R²⁷ R²⁸ R²⁹ R³⁰  1 h 25 ± 14 25 ± 14 25 ± 12 25 ± 12 25 ± 10 25 ± 9 25 ±8 25 ± 7 25 ± 6 25 ± 5  2 h 35 ± 18 35 ± 17 35 ± 16 35 ± 15 35 ± 14 35 ±13 35 ± 12 35 ± 11 35 ± 10 35 ± 10  8 h 65 ± 35 65 ± 32 65 ± 29 65 ± 2760 ± 25 65 ± 23 60 ± 21 65 ± 19 65 ± 17 65 ± 15 12 h ≧70 ≧72 ≧74 ≧76 ≧78≧80 ≧82 ≧84 ≧86 ≧88 24 h ≧75 ≧77 ≧79 ≧81 ≧83 ≧85 ≧87 ≧89 ≧90 ≧90 % R³¹R³² R³³ R³⁴ R³⁵ R³⁶ R³⁷ R³⁸ R³⁹ R⁴⁰  1 h  8 ± 7  8 ± 6  8 ± 5  8 ± 4 13± 12 13 ± 10 13 ± 8 13 ± 6 15 ± 10 15 ± 7  2 h 15 ± 14 15 ± 11 15 ± 8 15± 5 20 ± 23 20 ± 18 20 ± 13 20 ± 8 25 ± 15 25 ± 10  8 h 40 ± 34 40 ± 2640 ± 18 40 ± 10 45 ± 24 45 ± 18 45 ± 12 45 ± 6 50 ± 25 50 ± 15 12 h ≧50≧54 ≧58 ≧60 60 ± 29 60 ± 22 60 ± 15 60 ± 9 70 ± 25 70 ± 20 24 h ≧70 ≧70≧75 ≧75 ≧70 ≧75 ≧80 ≧85 ≧75 ≧80 % R⁴¹ R⁴² R⁴³ R⁴⁴ R⁴⁵ R⁴⁶ R⁴⁷ R⁴⁸ R⁴⁹R⁵⁰  1 h 15 ± 7 15 ± 5 20 ± 12 20 ± 9 20 ± 7 20 ± 5 25 ± 24 25 ± 18 25 ±12 25 ± 6  2 h 20 ± 10 25 ± 5 25 ± 15 25 ± 11 25 ± 9 25 ± 7 35 ± 30 35 ±27 35 ± 20 45 ± 11  8 h 50 ± 10 55 ± 5 60 ± 20 60 ± 15 60 ± 12 60 ± 1070 ± 35 70 ± 20 70 ± 15 70 ± 10 12 h 70 ± 15 75 ± 5 75 ± 30 75 ± 20 75 ±18 75 ± 13 80 ± 30 80 ± 25 80 ± 18 80 ± 13 24 h ≧90 ≧95 >95 >95 >95≧98 >95 >95 ≧98 ≧98

Suitable in vitro conditions are known to the skilled artisan. In thisregard it can be referred to, e.g., the Ph. Eur. Preferably, the invitro release profile is measured under the following conditions: 600 mlphosphate buffer (pH 6.8) at temperature of 37° C. with sinker (type 1or 2); rotation speed of the paddle: 75 min⁻¹.

Preferably, the release profile of the pharmaceutical dosage formaccording to the invention is stable upon storage, preferably uponstorage at elevated temperature, e.g. 37° C., for 3 months in sealedcontainers. In this regard “stable” means that when comparing theinitial release profile with the release profile after storage, at anygiven time point the release profiles deviate from one anotherabsolutely by not more than 20%, more preferably not more than 15%,still more preferably not more than 10%, yet more preferably not morethan 7.5%, most preferably not more than 5.0%. and in particular notmore than 2.5%.

Preferably, the pharmaceutical dosage form according to the invention ismonolithic. Preferably, the pharmaceutical dosage form is a monolithicmass.

In the manufacturing process of the pharmaceutical dosage form accordingto the invention, all polymers are preferably employed as powders.

Preferably, the pharmaceutical dosage form according to the invention isthermoformed, more preferably hot-melt extruded, although also othermethods of thermoforming may be used in order to manufacture thepharmaceutical dosage form according to the invention, such aspress-molding at elevated temperature or heating of tablets that weremanufactured by conventional compression in a first step and then heatedabove the softening temperature of the polymer in the tablet in a secondstep to form hard tablets. In this regards, thermoforming means formingor molding of a mass after the application of heat.

In a preferred embodiment, the pharmaceutical dosage form isthermoformed by hot-melt extrusion. The melt extruded strands arepreferably cut into monoliths, which are then preferably formed intotablets. In this regard, the term “tablets” is preferably not to beunderstood as pharmaceutical dosage forms being made by compression ofpowder or granules (compressi) but rather, as shaped extrudates.

In a preferred embodiment, the pharmaceutical dosage form has a totalweight within the range of 100±75 mg, more preferably 100±50 mg, mostpreferably 100±25 mg. In another preferred embodiment, thepharmaceutical dosage form has a total weight within the range of 200±75mg, more preferably 200±50 mg, most preferably 200±25 mg. In anotherpreferred embodiment, the pharmaceutical dosage form has a total weightwithin the range of 250±75 mg, more preferably 250±50 mg, mostpreferably 250±25 mg. In still another preferred embodiment, thepharmaceutical dosage form has a total weight within the range of 300±75mg, more preferably 300±50 mg, most preferably 300±25 mg. In yet anotherpreferred embodiment, the pharmaceutical dosage form has a total weightwithin the range of 400±75 mg, more preferably 400±50 mg, mostpreferably 400±25 mg.

In a preferred embodiment, the pharmaceutical dosage form has a totalweight within the range of 500±250 mg, more preferably 500±200 mg, mostpreferably 500±150 mg. In another preferred embodiment, thepharmaceutical dosage form has a total weight within the range of750±250 mg, more preferably 750±200 mg, most preferably 750±150 mg. Inanother preferred embodiment, the pharmaceutical dosage form has a totalweight within the range of 1000±250 mg, more preferably 1000±200 mg,most preferably 1000±150 mg. In still another preferred embodiment, thepharmaceutical dosage form has a total weight within the range of1250±250 mg, more preferably 1250±200 mg, most preferably 1250±150 mg.

The pharmaceutical dosage form according to the invention ischaracterized by excellent storage stability. Preferably, after storagefor 4 weeks at 40° C. and 75% rel. humidity, the content ofpharmacologically active compound amounts to at least 90%, morepreferably at least 91%, still more preferably at least 92%, yet morepreferably at least 93%, most preferably at least 94% and in particularat least 95%, of its original content before storage. Suitable methodsfor measuring the content of the pharmacologically active compound inthe pharmaceutical dosage form are known to the skilled artisan. In thisregard it is referred to the Eur. Ph. or the USP, especially to reversedphase HPLC analysis. Preferably, the pharmaceutical dosage form isstored in closed, preferably sealed containers, most preferably beingequipped with an oxygen scavenger, in particular with an oxygenscavenger that is effective even at low relative humidity.

In a preferred embodiment, after oral administration of thepharmaceutical dosage form according to the invention, in vivo theaverage peak plasma level (C_(max)) of the pharmacologically activecompound is on average reached after t_(max) 4.0±2.5 h, more preferablyafter t_(max) 4.0±2.0 h, still more preferably after t_(max) 4.0±1.5 h,most preferably after t_(max) 4.0±1.0 h and in particular after t_(max)4.0±0.5 h. In another preferred embodiment, after oral administration ofthe pharmaceutical dosage form according to the invention, in vivo theaverage peak plasma level (C_(max)) of the pharmacologically activecompound is on average reached after t_(max) 5.0±2.5 h, more preferablyafter t_(max) 5.0±2.0 h, still more preferably after t_(max) 5.0±1.5 h,most preferably after t_(max) 5.0±1.0 h and in particular after t_(max)5.0±0.5 h. In still another preferred embodiment, after oraladministration of the pharmaceutical dosage form according to theinvention, in vivo the average peak plasma level (C_(max)) of thepharmacologically active compound is on average reached after t_(max)6.0±2.5 h, more preferably after t_(max) 6.0±2.0 h, still morepreferably after t_(max) 6.0±1.5 h, most preferably after t_(max)6.0±1.0 h and in particular after t_(max) 6.0±0.5 h.

In a preferred embodiment, the average value for t_(1/2) of thepharmacologically active compound after oral administration of thepharmaceutical dosage form according to the invention in vivo is 4.0±2.5h, more preferably 4.0±2.0 h, still more preferably 4.0±1.5 h, mostpreferably 4.0±1.0 h, and in particular 4.0±0.5 h. In another preferredembodiment, the average value for t_(1/2) of the pharmacologicallyactive compound after oral administration of the pharmaceutical dosageform according to the invention in vivo is preferably 5.0±2.5 h, morepreferably 5.0±2.0 h, still more preferably 5.0±1.5 h, most preferably5.0±1.0 h, and in particular 5.0±0.5 h. In still another preferredembodiment, the average value for t_(1/2) of the pharmacologicallyactive compound after oral administration of the pharmaceutical dosageform according to the invention in vivo is preferably 6.0±2.5 h, morepreferably 6.0±2.0 h, still more preferably 6.0±1.5 h, most preferably6.0±1.0 h, and in particular 6.0±0.5 h.

Preferably, C_(max) of the pharmacologically active compound does notexceed 0.01 ng/ml, or 0.05 ng/ml, or 0.1 ng/ml, or 0.5 ng/ml, or 1.0ng/ml, or 2.5 ng/ml, or 5 ng/ml, or 10 ng/ml, or 20 ng/ml, or 30 ng/ml,or 40 ng/ml, or 50 ng/ml, or 75 ng/ml, or 100 ng/ml, or 150 ng/ml, or200 ng/ml, or 250 ng/ml, or 300 ng/ml, or 350 ng/ml, or 400 ng/ml, or450 ng/ml, or 500 ng/ml, or 750 ng/ml, or 1000 ng/ml.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains no substances which irritate the nasal passagesand/or pharynx, i.e. substances which, when administered via the nasalpassages and/or pharynx, bring about a physical reaction which is eitherso unpleasant for the patient that he/she does not wish to or cannotcontinue administration, for example burning, or physiologicallycounteracts taking of the corresponding active compound, for example dueto increased nasal secretion or sneezing. Further examples of substanceswhich irritate the nasal passages and/or pharynx are those which causeburning, itching, urge to sneeze, increased formation of secretions or acombination of at least two of these stimuli. Corresponding substancesand the quantities thereof which are conventionally to be used are knownto the person skilled in the art. Some of the substances which irritatethe nasal passages and/or pharynx are accordingly based on one or moreconstituents or one or more plant parts of a hot substance drug.Corresponding hot substance drugs are known per se to the person skilledin the art and are described, for example, in “PharmazeutischeBiologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner,2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982,pages 82 et seq. The corresponding description is hereby introduced as areference and is deemed to be part of the disclosure.

The pharmaceutical dosage form according to the invention furthermorepreferably contains no emetic. Emetics are known to the person skilledin the art and may be present as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof. The pharmaceutical dosageform according to the invention preferably contains no emetic based onone or more constituents of ipecacuanha (ipecac) root, for example basedon the constituent emetine, as are, for example, described in“Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr.Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag,Stuttgart, N.Y., 1982. The corresponding literature description ishereby introduced as a reference and is deemed to be part of thedisclosure. The pharmaceutical dosage form according to the inventionpreferably also contains no apomorphine as an emetic.

The pharmaceutical dosage form according to the invention preferablyalso contains no bitter substance. Bitter substances and the quantitieseffective for use may be found in US-2003/0064099 A1, the correspondingdisclosure of which should be deemed to be the disclosure of the presentapplication and is hereby introduced as a reference. Examples of bittersubstances are aromatic oils, such as peppermint oil, eucalyptus oil,bitter almond oil, menthol, fruit aroma substances, aroma substancesfrom lemons, oranges, limes, grapefruit or mixtures thereof, and/ordenatonium benzoate.

The pharmaceutical dosage form according to the invention accordinglypreferably contains neither substances which irritate the nasal passagesand/or pharynx, nor emetics, nor bitter substances.

Preferably, the pharmaceutical dosage form according to the inventioncontains no neuroleptics, for example a compound selected from the groupconsisting of haloperidol, promethacine, fluphenazine, perphenazine,levomepromazine, thioridazine, perazine, chlorpromazine,chlorprothixine, zuclopenthixol, flupentixol, prothipendyl, zotepine,benperidol, pipamperone, melperone and bromperidol.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains no pharmacologically active compound antagonists.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention does contain a pharmacologically activecompound antagonist. Pharmacologically active compound antagonistssuitable for a given pharmacologically active compound are known to theperson skilled in the art and may be present as such or in the form ofcorresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof. Thepharmaceutical dosage form according to the invention preferablycontains an opioid as pharmacologically active compound and an opioidantagonist as pharmacologically active compound antagonist, wherein theopioid antagonist is selected from the group consisting of naloxone,naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, ineach case optionally in the form of a corresponding physiologicallyacceptable compound, in particular in the form of a base, a salt orsolvate. Naloxone and nalmexone as well as their physiologicallyacceptable salts are preferred pharmacologically active compoundantagonists. The content of the pharmacologically active compoundantagonist in the pharmaceutical dosage form is not limited.

Besides the pharmacologically active compound, the anionic polymer andthe nonionic surfactant the pharmaceutical dosage form according to theinvention may contain further constituents, such as conventionalpharmaceutical excipients.

Preferably, the pharmaceutical dosage form according to the inventioncontains a plasticizer.

Preferred plasticizers are polyalkylene glycols, like polyethyleneglycol, triacetin, fatty acids, fatty acid esters, waxes and/ormicrocrystalline waxes. Particularly preferred plasticizers arepolyethylene glycols, such as PEG 6000.

Preferably, the content of the plasticizer is within the range of from0.1 to 30 wt.-%, more preferably 0.5 to 27.5 wt.-%, still morepreferably 1.0 to 25 wt.-%, yet more preferably 5 to 25 wt.-%, mostpreferably 10 to 20 wt.-% and in particular 12.5 to 17.5 wt.-%, based onthe total weight of the pharmaceutical dosage form.

In a preferred embodiment, the plasticizer is a polyalkylene glycolhaving a content within the range of 5±4 wt.-%, more preferably 5±3.5wt.-%, still more preferably 5±3 wt.-%, yet more preferably 5±2.5 wt.-%,most preferably 5±2 wt.-%, and in particular 5±1.5 wt.-%, based on thetotal weight of the pharmaceutical dosage form.

In another preferred embodiment, the plasticizer is a polyalkyleneglycol having a content within the range of 10±8 wt.-%, more preferably10±6 wt.-%, still more preferably 10±5 wt.-%, yet more preferably 10±4wt.-%, most preferably 10±3 wt.-%, and in particular 10±2 wt.-%, basedon the total weight of the pharmaceutical dosage form.

In still another preferred embodiment, the plasticizer is a polyalkyleneglycol having a content within the range of 15±8 wt.-%, more preferably15±6 wt.-%, still more preferably 15±5 wt.-%, yet more preferably 15±4wt.-%, most preferably 15±3 wt.-%, and in particular 15±2 wt.-%, basedon the total weight of the pharmaceutical dosage form.

Preferably, the relative weight ratio of the anionic polymer and theplasticizer is within the range of from 0.1:1 to 5.0:1, more preferablyfrom 0.2:1 to 4.0:1.

In a preferred embodiment, the relative weight ratio of the anionicpolymer and the plasticizer is at least 0.2:1, more preferably at least0.4:1, still more preferably at least 0.6:1, yet more preferably atleast 0.8:1, even more preferably at least 1.0:1, most preferably atleast 1.2:1, and in particular at least 1.4:1.

Preferably, the relative weight ratio of the nonionic surfactant and theplasticizer is within the range of from 0.1:1 to 5.0:1, more preferablyfrom 0.2:1 to 4.0:1.

In a preferred embodiment, the relative weight ratio of the nonionicsurfactant and the plasticizer is at least 0.2:1, more preferably atleast 0.4:1, still more preferably at least 0.6:1, yet more preferablyat least 0.8:1, even more preferably at least 1.0:1, most preferably atleast 1.2:1, and in particular at least 1.4:1.

Preferably, the relative weight ratio of the sum of anionic polymer andnonionic surfactant to the plasticizer is within the range of from 0.1:1to 7.0:1, more preferably from 0.2:1 to 6.5:1.

In a preferred embodiment, the relative weight ratio of the sum ofanionic polymer and nonionic surfactant to the plasticizer is at least0.2:1, more preferably at least 0.4:1, still more preferably at least0.6:1, yet more preferably at least 0.8:1, even more preferably at least1.0:1, most preferably at least 1.2:1, and in particular at least 1.4:1.In a particularly preferred embodiment, the relative weight ratio of thesum of anionic polymer and nonionic surfactant to the plasticizer is atleast 1.6:1, more preferably at least 1.8:1, still more preferably atleast 2.0:1, yet more preferably at least 2.2:1, even more preferably atleast 2.4:1, most preferably at least 2.6:1, and in particular at least2.8:1.

The pharmaceutical dosage form according to the invention may furthercontain an antioxidant.

Suitable antioxidants include ascorbic acid, α-tocopherol (vitamin E),butylhydroxyanisol, butylhydroxytoluene, salts of ascorbic acid (vitaminC), ascorbylic palmitate, monothioglycerine, coniferyl benzoate,nordihydroguajaretic acid, gallus acid esters, phosphoric acid, and thederivatives thereof, such as vitamin E-succinate or vitamin E-palmitateand/or sodium bisulphite, more preferably butylhydroxytoluene (BHT) orbutylhydroxyanisol (BHA) and/or α-tocopherol. A particularly preferredantioxidant is α-tocopherol.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention does either not contain any antioxidant, or contains oneor more antioxidants, wherein the content of all antioxidant(s) beingpresent in the dosage form preferably amounts to at most 5.0 wt.-%, morepreferably at most 2.5 wt.-%, more preferably at most 1.5 wt.-%, stillmore preferably at most 1.0 wt.-%, yet more preferably at most 0.5wt.-%, most preferably at most 0.4 wt.-% and in particular at most 0.3wt.-%, 0.2 wt.-% or 0.1 wt.-%, based on the total weight of thepharmaceutical dosage form.

The pharmaceutical dosage form according to the invention may furthercontain a free physiologically acceptable acid. The acid may be organicor inorganic, liquid or solid. Solid acids are preferred, particularlycrystalline organic or inorganic acids.

Preferably, the acid is free. This means that the acidic functionalgroups of the acid are not all together constituents of a salt of thepharmacologically active compound. If the pharmacologically activecompound is present as a salt of an acid, e.g. as hydrochloride, thepharmaceutical dosage form according to the invention preferablycontains as acid another, chemically different acid which is not presentas a constituent of the salt of the pharmacologically active compound.In other words, monoacids that form a salt with the pharmacologicallyactive compound are not to be considered as free acids in the meaning ofthe invention. When acid has more than a single acidic functional group(e.g. phosphoric acid), the acid may be present as a constituent of asalt of the pharmacologically active compound, provided that at leastone of the acidic functional groups of the acid is not involved in theformation of the salt, i.e. is free. Preferably, however, each and everyacidic functional group of acid is not involved in the formation of asalt with pharmacologically active compound. It is also possible,however, that free acid and the acid forming a salt withpharmacologically active compound are identical. Under thesecircumstances the acid is preferably present in molar excess compared topharmacologically active compound.

In a preferred embodiment, the acid contains at least one acidicfunctional group (e.g. —CO₂H, —SO₃H, —PO₃H₂, —OH and the like) having apK_(A) value within the range of 2.00±1.50, more preferably 2.00±1.25,still more preferably 2.00±1.00, yet more preferably 2.00±0.75, mostpreferably 2.00±0.50 and in particular 2.00±0.25. In another preferredembodiment, the acid contains at least one acidic functional grouphaving a pK_(A) value within the range of 2.25±1.50, more preferably2.25±1.25, still more preferably 2.25±1.00, yet more preferably2.25±0.75, most preferably 2.25±0.50 and in particular 2.25±0.25. Inanother preferred embodiment, the acid contains at least one acidicfunctional group having a pK_(A) value within the range of 2.50±1.50,more preferably 2.50±1.25, still more preferably 2.50±1.00, yet morepreferably 2.50±0.75, most preferably 2.50±0.50 and in particular2.50±0.25. In another preferred embodiment, the acid contains at leastone acidic functional group having a pK_(A) value within the range of2.75±1.50, more preferably 2.75±1.25, still more preferably 2.75±1.00,yet more preferably 2.75±0.75, most preferably 2.75±0.50 and inparticular 2.75±0.25. In another preferred embodiment, the acid containsat least one acidic functional group having a pK_(A) value within therange of 3.00±1.50, more preferably 3.00±1.25, still more preferably3.00±1.00, yet more preferably 3.00±0.75, most preferably 3.00±0.50 andin particular 3.00±0.25. In still another preferred embodiment, the acidcontains at least one acidic functional group having a pK_(A) valuewithin the range of 3.25±1.50, more preferably 3.25±1.25, still morepreferably 3.25±1.00, yet more preferably 3.25±0.75, most preferably3.25±0.50 and in particular 3.25±0.25.

In yet another preferred embodiment, the acid contains at least oneacidic functional group having a pK_(A) value within the range of4.50±1.50, more preferably 4.50±1.25, still more preferably 4.50±1.00,yet more preferably 4.50±0.75, most preferably 4.50±0.50 and inparticular 4.50±0.25. In yet another preferred embodiment, the acidcontains at least one acidic functional group having a pK_(A) valuewithin the range of 4.75±1.50, more preferably 4.75±1.25, still morepreferably 4.75±1.00, yet more preferably 4.75±0.75, most preferably4.75±0.50 and in particular 4.75±0.25. In yet another preferredembodiment, the acid contains at least one acidic functional grouphaving a pK_(A) value within the range of 5.00±1.50, more preferably5.00±1.25, still more preferably 5.00±1.00, yet more preferably5.00±0.75, most preferably 5.00±0.50 and in particular 5.00±0.25.

Preferably, the acid is an organic carboxylic or sulfonic acid,particularly a carboxylic acid. Multicarboxylic acids and/orhydroxy-carboxylic acids are especially preferred.

In case of multicarboxylic acids, the partial salts thereof are also tobe regarded as multicarboxylic acids, e.g. the partial sodium, potassiumor ammonium salts. For example, citric acid is a multicarboxylic acidhaving three carboxyl groups. As long as there remains at least onecarboxyl group protonated (e.g. sodium dihydrogen citrate or disodiumhydrogen citrate), the salt is to be regarded as a multicarboxylic acid.Preferably, however, all carboxyl groups of the multicarboxylic acid areprotonated.

Preferably, the acid is of low molecular weight, i.e., not polymerized.Typically, the molecular weight of the acid is below 500 g/mol.

Examples of acids include saturated and unsaturated monocarboxylicacids, saturated and unsaturated bicarboxylic acids, tricarboxylicacids, α-hydroxyacids and β-hydroxylacids of monocarboxylic acids,α-hydroxyacids and β-hydroxyacids of bicarboxylic acids, α-hydroxyacidsand β-hydroxyacids of tricarboxylic acids, ketoacids, α-ketoacids,β-ketoacids, of the polycarboxylic acids, of the polyhydroxymonocarboxylic acids, of the polyhydroxy bicarboxylic acids, of thepolyhydroxy tricarboxylic acids.

Preferably, the acid is selected from the group consisting ofbenzenesulfonic acid, citric acid, α-glucoheptonic acid, D-gluconicacid, glycolic acid, lactic acid, malic acid, malonic acid, mandelicacid, propanoic acid, succinic acid, tartaric acid (d, l, or dl), tosicacid (toluenesulfonic acid), valeric acid, palmitic acid, pamoic acid,sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid,glutaric acid, 4-chlorobenzenesulfonic acid, ethanedisulfonic acid,ethylsuccinic acid, fumaric acid, galactaric acid (mucic acid),D-glucuronic acid, 2-oxoglutaric acid, glycerophosphoric acid, hippuricacid, isethionic acid (ethanolsulfonic acid), lactobionic acid, maleicacid, maleinic acid, 1,5-naphthalene-disulfonic acid,2-naphthalenesulfonic acid, pivalic acid, terephthalic acid, thiocyanicacid, cholic acid, n-dodecyl sulfate, 3-hydroxy-2-naphthoic acid,1-hydroxy-2-naphthoic acid, oleic acid, undecylenic acid, ascorbic acid,(+)-camphoric acid, d-camphorsulfonic acid, dichloroacetic acid,ethanesulfonic acid, formic acid, methanesulfonic acid, nicotinic acid,orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharine,salicylic acid, gentisic acid, and/or 4-acetamidobenzoic acid.

Preferably, the acid is a multicarboxylic acid. More preferably, themulticarboxylic acid is selected from the group consisting of citricacid, maleic acid and fumaric acid.

Citric acid is particularly preferred.

The multicarboxylic acid, preferably citric acid, may be present in itsanhydrous form or as a solvate and hydrate, respectively, e.g., asmonohydrate.

If a free physiologically acceptable acid is contained in thepharmaceutical dosage form, it is preferably present in an amount of atmost 5.0 wt.-%, preferably at most 2.5 wt.-%, more at most 2.0 wt.-%, atmost 1.5 wt.-%, most preferably at most 1.0 wt.-% and in particular atmost 0.9 wt.-%, based on the total weight of the pharmaceutical dosageform.

The pharmaceutical dosage form according to the invention may alsocontain a natural, semi-synthetic or synthetic wax. Waxes with asoftening point of at least 50° C., more preferably 60° C. arepreferred. Carnauba wax and beeswax are particularly preferred,especially carnauba wax.

Preferably, the pharmaceutical dosage form according to the inventioncontains a coating, preferably a film-coating. Suitable coatingmaterials are known to the skilled person. Suitable coating materialsare commercially available, e.g. under the trademarks Opadry® andEudragit®.

Examples of suitable materials include cellulose esters and celluloseethers, such as methylcellulose (MC), hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC),sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC), celluloseacetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP);poly(meth)acrylates, such as am inoalkylmethacrylate copolymers,ethylacrylate methylmethacrylate copolymers, methacrylic acidmethylmethacrylate copolymers, methacrylic acid methylmethacrylatecopolymers; vinyl polymers, such as polyvinylpyrrolidone,polyvinyl-acetatephthalate, polyvinyl alcohol, polyvinylacetate; andnatural film formers, such as shellac.

In a particularly preferred embodiment, the coating is water-soluble. Ina preferred embodiment, the coating is based on polyvinyl alcohol, suchas polyvinyl alcohol-part. hydrolyzed, and may additionally containpolyethylene glycol, such as macrogol 3350, and/or pigments. In anotherpreferred embodiment, the coating is based onhydroxypropylmethylcellulose, preferably hypromellose type 2910 having aviscosity of 3 to 15 mPas.

The coating of the pharmaceutical dosage form can increase its storagestability.

The coating can be resistant to gastric juices and dissolve as afunction of the pH value of the release environment. By means of thiscoating, it is possible to ensure that the pharmaceutical dosage formaccording to the invention passes through the stomach undissolved andthe active compound is only released in the intestines. The coatingwhich is resistant to gastric juices preferably dissolves at a pH valueof between 5 and 7.5. Corresponding materials and methods for thedelayed release of active compounds and for the application of coatingswhich are resistant to gastric juices are known to the person skilled inthe art, for example from “Coated Pharmaceutical dosageforms—Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects,Test Methods and Raw Materials” by Kurt H. Bauer, K. Lehmann, Hermann P.Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm ScientificPublishers.

The pharmaceutical dosage form according to the invention is preferablytamper-resistant. Preferably, tamper-resistance is achieved based on themechanical properties of the pharmaceutical dosage form so thatcomminution is avoided or at least substantially impeded. According tothe invention, the term comminution means the pulverization of thepharmaceutical dosage form using conventional means usually available toan abuser, for example a pestle and mortar, a hammer, a mallet or otherconventional means for pulverizing under the action of force. Thus,tamper-resistance preferably means that pulverization of thepharmaceutical dosage form using conventional means is avoided or atleast substantially impeded.

Preferably, the mechanical properties of the pharmaceutical dosage formaccording to the invention, particularly its breaking strength,substantially rely on the presence and spatial distribution of theanionic polymer and the nonionic surfactant, although its/their merepresence does typically not suffice in order to achieve said properties.The advantageous mechanical properties of the pharmaceutical dosage formaccording to the invention may not automatically be achieved by simplyprocessing pharmacologically active compound, anionic polymer, andoptionally further excipients, such as the nonionic surfactant, by meansof conventional methods for the preparation of pharmaceutical dosageforms. In fact, usually suitable apparatuses must be selected for thepreparation and critical processing parameters must be adjusted,particularly pressure/force, temperature and time. Thus, even ifconventional apparatuses are used, the process protocols usually must beadapted in order to meet the required criteria.

Furthermore, tamper-resistance is achieved based on the poor solubilityproperties of the pharmaceutical dosage form in alcohol, especiallyethanol, thereby effectively preventing alcohol dose dumping.

The purpose of the anionic polymer that is contained in thepharmaceutical dosage form according to the invention is associated withthe tamper resistance of the pharmaceutical dosage form, especially whenthe pharmaceutical dosage form is intended by an abuser foradministration by a non-prescribed route, particularly intravenousadministration of a liquid extract.

In a preferred embodiment, when

subjecting a pharmaceutical dosage form (a) for 5 minutes in 5 mL ofcold water, or (b) to boiling water and boiling the tablet for 5minutes, respectively,closing the vessel with aluminum foil, boiling extraction only,drawing up the liquid into a syringe using a canula, preferably 0.80×40mm BL/LB; 21 G×1½″, through a cigarette filter, anddetermining the pharmacologically active compound content in the drawnliquid by HPLC analysis;the content of extracted pharmacologically active compound in theoverhead liquid amounts to at most 14.5 wt.-%, 14.0 wt.-%, 13.5 wt.-%,or 13.0 wt.-%, more preferably at most 12.5 wt.-%, 12.0 wt.-%, 11.5wt.-%, or 11.0 wt.-%, still more preferably at most 10.5 wt.-%, 10wt.-%, 9.5 wt.-%, or 9.0 wt.-%, yet more preferably at most 8.5 wt.-%,8.0 wt.-%, 7.5 wt.-%, or 7.0 wt.-%, even more preferably at most 6.5wt.-%, 6.0 wt.-%, 5.5 wt.-%, or 5.0 wt.-%, most more preferably at most4.5 wt.-%, 4.0 wt.-%, 3.5 wt.-%, or 3.0 wt.-%, and in particular at most2.5 wt.-%, 2.0 wt.-%, 1.5 wt.-%, or 1.0 wt.-%, relative to the originaltotal content of the pharmacologically active compound in thepharmaceutical dosage form, i.e. before it was subjected to theextraction test.

In a preferred embodiment, when

subjecting a pharmaceutical dosage form (a) for 5 minutes in 5 mL ofcold water, or (b) to boiling water and boiling the pharmaceuticaldosage form for 5 minutes, respectively,closing the vessel with aluminum foil, boiling extraction only,drawing up the liquid into a 10 mL syringe using a canula, preferably0.80×40 mm BL/LB; 21 G×1½″, through a cigarette filter, anddetermining the pharmacologically active compound content in the drawnliquid by HPLC analysis.the total amount of extracted pharmacologically active compound in theoverhead liquid amounts toat most 115 mg, 110 mg, 105 mg, or 100 mg, more preferably at most 95mg, 90 mg, 85 mg, or 80 mg, still more preferably at most 75 mg, 70 mg,65 mg, or 60 mg, yet more preferably at most 55 mg, 50 mg, 47.5 mg, or45 mg, even more preferably at most 42.5 mg, 40 mg, 37.5 mg, or 35 mg,most more preferably at most 32.5 mg, 30 mg, 27.5 mg, or 25 mg, and inparticular at most 22.5 mg, 20 mg, 17.5 mg, or 15 mg; orat most 14.5 mg, 14.0 mg, 13.5 mg, or 13.0 mg, more preferably at most12.5 mg, 12.0 mg, 11.5 mg, or 11.0 mg, still more preferably at most10.5 mg, 10 mg, 9.5 mg, or 9.0 mg, yet more preferably at most 8.5 mg,8.0 mg, 7.5 mg, or 7.0 mg, even more preferably at most 6.5 mg, 6.0 mg,5.5 mg, or 5.0 mg, most more preferably at most 4.5 mg, 4.0 mg, 3.5 mg,or 3.0 mg, and in particular at most 2.5 mg, 2.0 mg, 1.5 mg, or 1.0 mg.

In a preferred embodiment, when

subjecting a pharmaceutical dosage form (a) for 30 minutes to 30 mL ofsolvent with continuous shaking, or (b) giving a pharmaceutical dosageform in 30 mL of purified water, heating the water until boiling andshaking for 30 minutes, during the slow cooling of the water;supplementing lost water, if any, anddetermining the pharmacologically active compound content in theoverhead liquid by HPLC analysis;the content of extracted pharmacologically active compound in theoverhead liquid amounts to at most 40 wt.-%, more preferably at most 35wt.-%, still more preferably at most 30 wt.-%, yet more preferably atmost 25 wt.-% or 24 wt.-%, even more preferably at most 23 wt.-%, 22wt.-%, 21 wt.-% or 20 wt.-%, most preferably at most 19 wt.-%, 18 wt.-%,17 wt.-%, or 16 wt.-%, and in particular at most 15.5 wt.-%, 15.0 wt.-%,12 wt.-%, or 10 wt.-%, relative to the original total content of thepharmacologically active compound in the pharmaceutical dosage form,i.e. before it was subjected to the extraction test.

In a preferred embodiment, when

subjecting a pharmaceutical dosage form (a) for 30 minutes to 30 mL ofsolvent with continuous shaking, or (b) giving a pharmaceutical dosageform in 30 mL of purified water, heating the water until boiling andshaking for 30 minutes, during the slow cooling of the water;supplementing lost water, if any, anddetermining the pharmacologically active compound content in theoverhead liquid by HPLC analysis;the total amount of extracted pharmacologically active compound in theoverhead liquid amounts toat most 200 mg, 190 mg, 180 mg, or 170 mg, more preferably at most 160mg, 150 mg, 140 mg, or 135 mg, still more preferably at most 130 mg, 125mg, 120 mg, or 110 mg, yet more preferably at most 105 mg or 100 mg,even more preferably at most 95 mg or 90 mg, most more preferably atmost 85 mg or 80 mg, and in particular at most 75 mg, 70 mg, 65 mg, or60 mg; orat most 55 mg, 50 mg, 47.5 mg, or 45 mg, more preferably at most 42.5mg, 40 mg, 37.5 mg, or 35 mg, still more preferably at most 32.5 mg, 30mg, 27.5 mg, or 25 mg, yet more preferably at most 22.5 mg or 20 mg,even more preferably at most 17.5 mg or 15 mg, most more preferably atmost 14 mg or 13 mg, and in particular at most 12.5 mg, 12 mg, 11.5 mg,11 mg, 10.5 mg or 10 mg.

Preferably, when a pharmaceutical dosage form according to the inventionis treated with a commercial coffee mill, preferably type Bosch MKM6000,for 2 minutes, at least 40 wt.-%, more preferably at least 50 wt.-%,still more preferably at least 60 wt.-%, yet more preferably at least 65wt.-%, even more preferably at least 70 wt.-%, most preferably at least75 wt.-%, and in particular at least 80 wt.-%, of the total weight ofthe thus obtained material does not pass a sieve having a mesh size of1.000 mm.

In a preferred embodiment, when a pharmaceutical dosage form accordingto the invention is treated with a commercial coffee mill, preferablytype Bosch MKM6000, for 2 minutes, it either remains intact and in onepiece, or it is split into at most 10, preferably at most 7 or 8, morepreferably at most 5 or 6, still more preferably at most 4, mostpreferably at most 3, and in particular at most 2 pieces.

The pharmaceutical dosage form according to the invention has a breakingstrength of at least 300 N, preferably at least 400 N, more preferablyat least 500 N, still more preferably at least 750 N, yet morepreferably at least 1000 N, most preferably at least 1250 N and inparticular at least 1500 N.

The “breaking strength” (resistance to crushing) of a pharmaceuticaldosage form is known to the skilled person. In this regard it can bereferred to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, EditioCantor Verlag Aulendorf, 2002; H Liebermann et al., Pharmaceuticaldosage forms: Tablets, Vol. 2, Informa Healthcare; 2 edition, 1990; andEncyclopedia of Pharmaceutical Technology, Informa Healthcare; 1edition.

For the purpose of the specification, the breaking strength ispreferably defined as the amount of force that is necessary in order tofracture the pharmaceutical dosage form (=breaking force). Therefore,for the purpose of the specification the pharmaceutical dosage form doespreferably not exhibit the desired breaking strength when it breaks,i.e., is fractured into at least two independent parts that areseparated from one another. In another preferred embodiment, however,the pharmaceutical dosage form is regarded as being broken if the forcedecreases by 25% (threshold value) of the highest force measured duringthe measurement (see below).

The pharmaceutical dosage forms according to the invention aredistinguished from conventional pharmaceutical dosage forms in that, dueto their breaking strength, they cannot be pulverized by the applicationof force with conventional means, such as for example a pestle andmortar, a hammer, a mallet or other usual means for pulverization, inparticular devices developed for this purpose (tablet crushers). In thisregard “pulverization” means crumbling into small particles that wouldimmediately release the pharmacologically active compound in a suitablemedium. Avoidance of pulverization virtually rules out oral orparenteral, in particular intravenous or nasal abuse.

Conventional tablets typically have a breaking strength well below 200 Nin any direction of extension. The breaking strength of conventionalround tablets may be estimated according to the following empiricalformula: Breaking Strength [in N]=10×Diameter Of The Tablet [in mm].Thus, according to said empirical formula, a round tablet having abreaking strength of at least 300 N would require a diameter of at least30 mm). Such a tablet, however, could not be swallowed. The aboveempirical formula preferably does not apply to the pharmaceutical dosageforms of the invention, which are not conventional but rather special.

Further, the actual mean chewing force is about 220 N (cf., e.g., P. A.Proeschel et al., J Dent Res, 2002, 81(7), 464-468). This means thatconventional tablets having a breaking strength well below 200 N may becrushed upon spontaneous chewing, whereas the pharmaceutical dosageforms according to the invention may not.

Still further, when applying a gravitational acceleration of about 9.81m/s², 300 N correspond to a gravitational force of more than 30 kg, i.e.the pharmaceutical dosage forms according to the invention canpreferably withstand a weight of more than 30 kg without beingpulverised.

Methods for measuring the breaking strength of a pharmaceutical dosageform are known to the skilled artisan. Suitable devices are commerciallyavailable.

For example, the breaking strength (resistance to crushing) can bemeasured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08“Resistance to Crushing of Tablets”. The test is intended to determine,under defined conditions, the resistance to crushing of tablets,measured by the force needed to disrupt them by crushing. The apparatusconsists of 2 jaws facing each other, one of which moves towards theother. The flat surfaces of the jaws are perpendicular to the directionof movement. The crushing surfaces of the jaws are flat and larger thanthe zone of contact with the tablet. The apparatus is calibrated using asystem with a precision of 1 Newton. The tablet is placed between thejaws, taking into account, where applicable, the shape, the break-markand the inscription; for each measurement the tablet is oriented in thesame way with respect to the direction of application of the force (andthe direction of extension in which the breaking strength is to bemeasured). The measurement is carried out on 10 tablets, taking carethat all fragments of tablets have been removed before eachdetermination. The result is expressed as the mean, minimum and maximumvalues of the forces measured, all expressed in Newton.

A similar description of the breaking strength (breaking force) can befound in the USP. The breaking strength can alternatively be measured inaccordance with the method described therein where it is stated that thebreaking strength is the force required to cause a tablet to fail (i.e.,break) in a specific plane. The tablets are generally placed between twoplatens, one of which moves to apply sufficient force to the tablet tocause fracture. For conventional, round (circular cross-section)tablets, loading occurs across their diameter (sometimes referred to asdiametral loading), and fracture occurs in the plane. The breaking forceof tablets is commonly called hardness in the pharmaceutical literature;however, the use of this term is misleading. In material science, theterm hardness refers to the resistance of a surface to penetration orindentation by a small probe. The term crushing strength is alsofrequently used to describe the resistance of tablets to the applicationof a compressive load. Although this term describes the true nature ofthe test more accurately than does hardness, it implies that tablets areactually crushed during the test, which is often not the case.

In a preferred embodiment of the invention, the breaking strength(resistance to crushing) is measured in accordance with WO 2005/016313,WO 2005/016314, and WO 2006/082099, which can be regarded as amodification of the method described in the Eur. Ph. The apparatus usedfor the measurement is preferably a “Zwick Z 2.5” materials tester,F_(max)=2.5 kN with a maximum draw of 1150 mm, which should be set upwith one column and one spindle, a clearance behind of 100 mm and a testspeed adjustable between 0.1 and 800 mm/min together with testControlsoftware. Measurement is performed using a pressure piston with screw-ininserts and a cylinder (diameter 10 mm), a force transducer, F_(max). 1kN, diameter=8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1,with manufacturers test certificate M according to DIN 55350-18 (Zwickgross force F_(max)=1.45 kN) (all apparatus from Zwick GmbH & Co. KG,Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order NoBTC-LC 0050N. P01 for the force transducer, Order No BO 70000 S06 forthe centering device.

In another preferred embodiment of the invention, the breaking strengthis measured by means of a breaking strength tester e.g. Sotax®, typeHT100 or type HT1 (Allschwil, Switzerland). Both, the Sotax® HT100 andthe Sotax® HT1 can measure the breaking strength according to twodifferent measurement principles: constant speed (where the test jaw ismoved at a constant speed adjustable from 5-200 mm/min) or constantforce (where the test jaw increases force linearly adjustable from 5-100N/sec). In principle, both measurement principles are suitable formeasuring the breaking strength of the pharmaceutical dosage formaccording to the invention. Preferably, the breaking strength ismeasured at constant speed, preferably at a constant speed of 120mm/min.

In a preferred embodiment, the pharmaceutical dosage form is regarded asbeing broken if it is fractured into at least two separate pieces.

The pharmaceutical dosage form according to the invention preferablyexhibits mechanical strength over a wide temperature range, in additionto the breaking strength (resistance to crushing) optionally alsosufficient hardness, impact resistance, impact elasticity, tensilestrength and/or modulus of elasticity, optionally also at lowtemperatures (e.g. below −24° C., below −40° C. or in liquid nitrogen),for it to be virtually impossible to pulverize by spontaneous chewing,grinding in a mortar, pounding, etc. Thus, preferably, the comparativelyhigh breaking strength of the pharmaceutical dosage form according tothe invention is maintained even at low or very low temperatures, e.g.,when the pharmaceutical dosage form is initially chilled to increase itsbrittleness, for example to temperatures below −25° C., below −40° C. oreven in liquid nitrogen.

The pharmaceutical dosage form according to the invention ischaracterized by a certain degree of breaking strength. This does notmean that the pharmaceutical dosage form must also exhibit a certaindegree of hardness. Hardness and breaking strength are differentphysical properties. Therefore, the tamper resistance of thepharmaceutical dosage form does not necessarily depend on the hardnessof the pharmaceutical dosage form. For instance, due to its breakingstrength, impact strength, elasticity modulus and tensile strength,respectively, the pharmaceutical dosage form can preferably be deformed,e.g. plastically, when exerting an external force, for example using ahammer, but cannot be pulverized, i.e., crumbled into a high number offragments. In other words, the pharmaceutical dosage form according tothe invention is characterized by a certain degree of breaking strength,but not necessarily also by a certain degree of form stability.

Therefore, in the meaning of the specification, a pharmaceutical dosageform that is deformed when being exposed to a force in a particulardirection of extension but that does not break (plastic deformation orplastic flow) is preferably to be regarded as having the desiredbreaking strength in said direction of extension.

Preferably, the pharmaceutical dosage form according to the invention

-   -   has a breaking strength of at least 400 N, more preferably at        least 500 N, still more preferably at least 750 N, and most        preferably at least 1000 N; and/or    -   comprises a pharmacologically active compound selected from        opioids, more preferably from hydromorphone, oxycodone,        oxymorphone, tapentadol and the physiologically acceptable salts        thereof; and/or    -   comprises an anionic polymer derived from a monomer composition        comprising an ethylenically unsaturated monomer selected from        (alk)acrylic acids, (alk)acrylic anhydrides, alkyl        (alk)acrylates, or a combination thereof, in particular acrylic        acid, and optionally at least one cross-linking agent selected        from the group consisting of allyl sucrose, allyl        pentaerythritol, divinyl glycol, divinyl polyethylene glycol and        (meth)acrylic acid esters of diols; and/or    -   comprises the anionic polymer in an amount of at least 25 wt.-%,        preferably at least 30 wt.-% or at least 32 wt.-%, based on the        total weight of the pharmaceutical dosage form; and/or    -   comprises a nonionic surfactant,        -   (i) preferably a copolymer of ethylene oxide and propylene            oxide, more preferably a block copolymer according to            general formula (I-a)

-   -   -   -   wherein a and c are each independently an integer of                from 5 to 300 and b is an integer of from 10 to 100;                and/or a block copolymer according to general formula                (I-b)

-   -   -   -   wherein e, f, g and h are each independently an integer                of from 1 to 150, and i, j, k and l are each                independently an integer of from 2 to 50;

        -   (ii) which is preferably contained in the pharmaceutical            dosage form in an amount of at least 10 wt.-%, more            preferably at least 15 wt.-%, and most preferably 15 to 40            wt.-%, based on the total weight of the pharmaceutical            dosage form; and/or

        -   (iii) which preferably exhibits an HLB value of at least 20,            more preferably at least 24; and/or

    -   is configured for oral administration, preferably one daily or        twice daily; and/or

    -   either does not contain any polyalkylene oxide having an average        molecular weight of at least 200,000 g/mol, preferably of at        least 50,000 g/mol; or wherein the total content of polyalkylene        oxide(s) having an average molecular weight of at least 200,000        g/mol or at least 50,000 g/mol, respectively, is 20 wt.-%,        preferably 10 wt.-%, based on the total weight of the        pharmaceutical dosage form; and/or

    -   optionally, contains a plasticizer, preferably polyethylene        glycol; and/or

    -   optionally, contains an additional matrix polymer, preferably a        cellulose ether, more preferably HPMC.

The pharmaceutical dosage form according to the invention may beproduced by different processes, the particularly preferred of which areexplained in greater detail below. Several suitable processes havealready been described in the prior art. In this regard it can bereferred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO2006/082097, and WO 2006/082099.

The invention also relates to pharmaceutical dosage forms that areobtainable by any of the processes described here below.

In general, the process for the production of the pharmaceutical dosageform according to the invention preferably comprises the followingsteps:

-   (a) mixing all ingredients;-   (b) optionally pre-forming the mixture obtained from step (a),    preferably by applying heat and/or force to the mixture obtained    from step (a), the quantity of heat supplied preferably not being    sufficient to heat the matrix material up to its softening point;-   (c) hardening the mixture by applying heat and force, it being    possible to supply the heat during and/or before the application of    force and the quantity of heat supplied being sufficient to heat the    matrix material at least up to its softening point;-   (d) optionally singulating the hardened mixture;-   (e) optionally shaping the pharmaceutical dosage form; and-   (f) optionally providing a film coating.

Heat may be supplied directly, e.g. by contact or by means of hot gassuch as hot air, or with the assistance of ultrasound, microwaves and/orradiation. Force may be applied and/or the pharmaceutical dosage formmay be shaped for example by direct tabletting or with the assistance ofa suitable extruder, particularly by means of a screw extruder equippedwith two screws (twin-screw-extruder) or by means of a planetary gearextruder.

The final shape of the pharmaceutical dosage form may either be providedduring the hardening of the mixture by applying heat and force (step(c)) or in a subsequent step (step (e)). In both cases, the mixture ofall components is preferably in the plastified state, i.e. preferably,shaping is performed at a temperature at least above the softening pointof the matrix material. However, extrusion at lower temperatures, e.g.ambient temperature, is also possible and may be preferred.

Shaping can be performed, e.g., by means of a tabletting presscomprising die and punches of appropriate shape.

A particularly preferred process for the manufacture of thepharmaceutical dosage form of the invention involves hot-melt extrusion.In this process, the pharmaceutical dosage form according to theinvention is produced by thermoforming with the assistance of anextruder, preferably without there being any observable consequentdiscoloration of the extrudate. It has been surprisingly found that acidis capable of suppressing discoloration. In the absence of acid, theextrudate tends to develop beige to yellowish coloring whereas in thepresence of acid the extrudates are substantially colorless, i.e. white.

This process is characterized in that

-   a) all components are mixed,-   b) the resultant mixture is heated in the extruder at least up to    the softening point of the matrix material and extruded through the    outlet orifice of the extruder by application of force,-   c) the still plastic extrudate is singulated and formed into the    pharmaceutical dosage form or-   d) the cooled and optionally reheated singulated extrudate is formed    into the pharmaceutical dosage form.

Mixing of the components according to process step a) may also proceedin the extruder.

The components may also be mixed in a mixer known to the person skilledin the art. The mixer may, for example, be a roll mixer, shaking mixer,shear mixer or compulsory mixer.

The, preferably molten, mixture which has been heated in the extruder atleast up to the softening point of matrix material is extruded from theextruder through a die with at least one bore.

The process according to the invention requires the use of suitableextruders, preferably screw extruders. Screw extruders which areequipped with two screws (twin-screw-extruders) are particularlypreferred.

The extrusion is preferably performed so that the expansion of thestrand due to extrusion is not more than 30%, i.e. that when using a diewith a bore having a diameter of e.g. 6 mm, the extruded strand shouldhave a diameter of not more than 8 mm. More preferably, the expansion ofthe strand is not more than 25%, still more preferably not more than20%, most preferably not more than 15% and in particular not more than10%.

Preferably, extrusion is performed in the absence of water, i.e., nowater is added. However, traces of water (e.g., caused by atmospherichumidity) may be present.

The extruder preferably comprises at least two temperature zones, withheating of the mixture at least up to the softening point of the matrixmaterial proceeding in the first zone, which is downstream from a feedzone and optionally mixing zone. The throughput of the mixture ispreferably from 1.0 kg to 15 kg/hour. In a preferred embodiment, thethroughput is from 1 to 3.5 kg/hour. In another preferred embodiment,the throughput is from 4 to 15 kg/hour.

In a preferred embodiment, the die head pressure is within the range offrom 2 to 100 bar. In a preferred embodiment, the die head pressure iswithin the range of from 25 to 100 bar. In another preferred embodiment,the die head pressure is within the range of from 2 to 25 bar. The diehead pressure can be adjusted inter alia by die geometry, temperatureprofile and extrusion speed.

The die geometry or the geometry of the bores is freely selectable. Thedie or the bores may accordingly exhibit a round, oblong or ovalcross-section, wherein the round cross-section preferably has a diameterof 0.1 mm to 15 mm and the oblong cross-section preferably has a maximumlengthwise extension of 21 mm and a crosswise extension of 10 mm.Preferably, the die or the bores have a round cross-section. The casingof the extruder used according to the invention may be heated or cooled.The corresponding temperature control, i.e. heating or cooling, is soarranged that the mixture to be extruded exhibits at least an averagetemperature (product temperature) corresponding to the softeningtemperature of the matrix material and does not rise above a temperatureat which the pharmacologically active compound to be processed may bedamaged. Preferably, the temperature of the mixture to be extruded isadjusted to below 180° C., preferably below 150° C., but at least to thesoftening temperature of matrix material. Typical extrusion temperaturesare 120° C. and 130° C.

In a preferred embodiment, the extruder torque is within the range offrom 30 to 95%. Extruder torque can be adjusted inter alia by diegeometry, temperature profile and extrusion speed.

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are preferablysingulated. This singulation may preferably be performed by cutting upthe extrudates by means of revolving or rotating knives, water jetcutters, wires, blades or with the assistance of laser cutters.

Preferably, intermediate or final storage of the optionally singulatedextrudate or the final shape of the pharmaceutical dosage form accordingto the invention is performed under oxygen-free atmosphere which may beachieved, e.g., by means of oxygen-scavengers.

The singulated extrudate may be press-formed into tablets in order toimpart the final shape to the pharmaceutical dosage form.

The application of force in the extruder onto the at least plasticizedmixture is adjusted by controlling the rotational speed of the conveyingdevice in the extruder and the geometry thereof and by dimensioning theoutlet orifice in such a manner that the pressure necessary forextruding the plasticized mixture is built up in the extruder,preferably immediately prior to extrusion. The extrusion parameterswhich, for each particular composition, are necessary to give rise to apharmaceutical dosage form with desired mechanical properties, may beestablished by simple preliminary testing.

For example but not limiting, extrusion may be performed by means of atwin-screw-extruder type ZSE 18 or ZSE27 (Leistritz, Nürnberg, Germany),screw diameters of 18 or 27 mm. Screws having eccentric ends may beused. A heatable die with a round bore having a diameter of 4, 5, 6, 7,8, 9, or 10 mm may be used. The extrusion parameters may be adjustede.g. to the following values: rotational speed of the screws: 120 Upm;delivery rate 2 kg/h for a ZSE 18 or 8 kg/h for a ZSE27; producttemperature: in front of die 125° C.; temperature of the die 135° C.;and jacket temperature: 110° C.

Preferably, extrusion is performed by means of twin-screw-extruders orplanetary-gear-extruders, twin-screw extruders (co-rotating orcontra-rotating) being particularly preferred.

The pharmaceutical dosage form according to the invention is preferablyproduced by thermoforming with the assistance of an extruder without anyobservable consequent discoloration of the extrudates.

The process for the preparation of the pharmaceutical dosage formaccording to the invention is preferably performed continuously.Preferably, the process involves the extrusion of a homogeneous mixtureof all components. It is particularly advantageous if the thus obtainedintermediate, e.g. the strand obtained by extrusion, exhibits uniformproperties. Particularly desirable are uniform density, uniformdistribution of the active compound, uniform mechanical properties,uniform porosity, uniform appearance of the surface, etc. Only underthese circumstances the uniformity of the pharmacological properties,such as the stability of the release profile, may be ensured and theamount of rejects can be kept low.

A further aspect of the invention relates to the use of apharmacologically active compound in combination with an anionic polymerfor the manufacture of the pharmaceutical dosage form as described abovefor the treatment of pain, preferably moderate to severe pain such asmoderate to severe low back pain.

A further aspect of the invention relates to the use of a pharmaceuticaldosage form as described above for avoiding or hindering the abuse ofthe pharmacologically active compound contained therein.

A further aspect of the invention relates to the use of a pharmaceuticaldosage form as described above for avoiding or hindering theunintentional overdose of the pharmacologically active compoundcontained therein.

In this regard, the invention also relates to the use of apharmacologically active compound as described above and/or an anionicpolymer as described above for the manufacture of the pharmaceuticaldosage form according to the invention for the prophylaxis and/or thetreatment of a disorder, thereby preventing an overdose of thepharmacologically active compound, particularly due to comminution ofthe pharmaceutical dosage form by mechanical action.

Further, the invention relates to a method for the prophylaxis and/orthe treatment of a disorder comprising the administration of thepharmaceutical dosage form according to the invention, therebypreventing an overdose of the pharmacologically active compound,particularly due to comminution of the pharmaceutical dosage form bymechanical action. Preferably, the mechanical action is selected fromthe group consisting of chewing, grinding in a mortar, pounding, andusing apparatuses for pulverizing conventional pharmaceutical dosageforms.

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

General Procedure:

Carbopol 71 G, tramadol hydrochloride and all other excipients wereweighted and sieved to each other.

The powder was mixed and dosed gravimetrically to an extruder. Hot-meltextrusion (revolution speed 100 rpm) was performed by means of a twinscrew extruder of type ZSE27 micro PH 40D (Leistritz, Nürnberg, Germany)that was equipped with a heatable round die having a diameter of 10 mm(cutting length 6-7 mm or 7-8 mm).

The hot extrudate was cooled by ambient air and the cooled extrusionstrand was comminuted to cut pieces. The cut pieces were shaped by meansof an excenter press which was equipped with a round punch.

The breaking strength of the pharmaceutical dosage forms was measured bymeans of a Sotax® HT100. A tablet was regarded as failing the breakingstrength test when during the measurement the force dropped below thethreshold value of 25% of the maximum force that was observed during themeasurement, regardless of whether the pharmaceutical dosage form wasfractured into separate pieces or not. All values are given as a mean of10 measurements.

The in vitro release profile of tramadol hydrochloride was measured in600 ml phosphate buffer (pH 6.8) at temperature of 37° C. with sinker(type 1 or 2). The rotation speed of the paddle was adjusted to 75/min.

EXAMPLE 1 a) Composition

Tablets having the following compositions were prepared:

I-1 I-2 I-3 I-4 mg wt.-% mg mg mg wt.-% mg wt.-% Tramadol HCl 80.0 13.380.0 13.3 80.0 13.3 80.0 13.3 Carbopol 71 G 185.0 30.85 185.0 30.85222.0 37.0 222.0 37.0 Poloxamer 407 (Lutrol ® F127) 185.0 30.85 — —148.0 24.7 — — Poloxamer 188 (Lutrol ® F68) — — 185.0 30.85 — — 148.024.7 HPMC 100,000 mPa · s 60.0 10.0 60.0 10.0 60.0 10.0 60.0 10.0Macrogol 6,000 90.0 15.0 90.0 15.0 90.0 15.0 90.0 15.0 Σ 600.0 100.0600.0 100.0 600.0 100.0 600.0 100.0 C-1 mg wt.-% Tramadol HCl 80.0 13.3Polyethylene Oxide M_(w) 7 × 10⁶ 370.0 61.7 HPMC 100,000 mPa · s 60.010.0 Macrogol 6,000 90.0 15.0 Σ 600.0 100.0

b) Hot-Melt Extrusion

The following extrusion parameters were adjusted and measured,respectively:

I-1 I-2 I-3 I-4 C-1 diameter of die [mm] 10 10 10 10 10 throughput[kg/h] 3.5 3.5 3.5 3.5 3.5 melt temperature [° C.] 116 115 117 115 98performance (%) 21 22 45 49 54 melt pressure [bar] 3 5 8 12 42 stranddiameter [mm] 10.3 12.2 10.5 10.5 9.9 cutting length [mm] 7.1-7.47.0-8.5 6.5-6.8 6-7 7.5

Crude extrudates having the following weights and dimensions wereobtained:

n = 10 I-1 I-2 I-3 I-4 C-1 weight [mg] min 584 578 577 575 599 max 629628 624 625 627 average 612 597 602 609 613 length [mm] min 6.95 6.396.30 6.52 6.45 max 7.46 7.01 7.33 7.40 7.54 average 7.26 6.68 6.66 6.947.12 diameter [mm] min 9.16 10.32 9.21 9.86 9.73 max 10.75 11.25 11.1110.92 10.12 average 9.75 10.79 10.33 10.44 9.97

c) Formation of Tablets from Extrudates

Tablets were manufactured from the crude extrudates by means of a roundpunch having the following dimensions (no engraving):

Example Form of punch round biconcave, round, diameter 12 mm, radius ofcurvature 9 mm

Tablets having the following weights and dimensions were obtained:

n = 10 I-1 I-2 I-3 I-4 C-1 thickness min 6.61 6.31 6.08 6.17 6.27 [mm]max 6.87 6.55 6.79 6.70 6.81 average 6.72 6.43 6.43 6.41 6.53 diameter[mm] min 11.68 11.61 11.46 11.35 11.56 max 12.03 12.09 12.05 11.98 11.86average 11.90 11.90 11.67 11.66 11.71

d) In-Vitro Release

measuring point Dissolution % (DS) I-1 I-2 I-3 I-4 C-1 after 60 min 1314 16 16 21 after 120 min 20 22 25 25 33 after 480 min 46 51 57 57 76after 720 min 59 64 73 75 90 after 1440 min 82 88 94 100 101

measuring point Dissolution % (0.1N HCl) I-1 I-2 I-3 I-4 C-1 after 60min 19 19 16 18 20 after 120 min 27 28 24 26 31 after 480 min 56 60 5158 78 after 720 min 68 75 65 73 95 after 1440 min 90 95 90 95 102

e) Tamper Resistance Breaking Strength

breaking strength [N] I-1 I-2 I-3 I-4 C-1 Sotax ® HT100 318 N 877 N≧1000 N ≧1000 N ≧1000 N

The corresponding force-displacement diagrams of examples I-1, I-2, I-3,I-4 and C are displayed as FIGS. 1-A, 1-B, 1-C, 1-D and 1-E,respectively.

The deviating curve in FIG. 1-C represents a measurement error (tabletdisplaced).

f) Tamper Resistance Extractability

The extractable content of pharmacologically active compound wasdetermined by

-   (i) subjecting a tablet (a) for 30 minutes to 30 mL of solvent with    continuous shaking, or (b) giving a tablet in 30 mL of purified    water, heating the water until boiling and shaking for 30 minutes,    during the slow cooling of the water;-   (ii) supplementing lost water, if any, and-   (iii) determining the pharmacologically active compound content in    the overhead liquid by HPLC analysis.

The syringeable content of pharmacologically active compound wasdetermined by

-   (i) subjecting a tablet (a) for 5 minutes in 5 mL of cold water,    or (b) to boiling water and boiling the tablet for 5 minutes,    respectively,-   (ii) closing the vessel with aluminum foil, boiling extraction only,-   (iii) drawing up the liquid into a syringe using a canula through a    cigarette filter, and-   (iv) determining the pharmacologically active compound content in    the drawn liquid by HPLC analysis.

The results are shown in the table here below:

content [wt.-%] I-1 I-2 I-3 I-4 C-1 faultless tablet 90.4 95.7 94.7 95.899.6 extraction cold water 9.7 9.9 8.6 9.3 13.9 extraction boiling water18.6 21.5 15.1 14.9 25.7 extraction water/ethanol 60/40 v/v 8.4 8.3 8.69.6 9.4 drawn up into syringe 2.9 10.8 3.2 6.8 2.6 (faultless tablet)drawn up into syringe 8.1 7.2 3.4 5.5 10.8 (ground tablet)¹⁾ ¹⁾householdcoffee mill, type Bosch MKM6000, 180W, type KM 13; grinding time: 2minutes

g) Tamper Resistance Hammer Impact

The test was performed by means of a free falling weight testing deviceType 40-550-001, 40-550-011 ff, Coesfeld GmbH & Co. KG, Germany. Thefollowing parameters were set:

Falling height: 1000 mm±1%Falling weight: 500 g±2%Form of falling weight: 25 mm×25 mmPosition of sample: loosely positioned in the center of the sampleholder

The measuring result was qualified according to the following scale:

-   -   (A) tablet apparently undamaged    -   (B) tablet has been compressed but is widely undamaged    -   (C) tablet has been compressed and is lacerated at its edges    -   (D) tablet has been disrupted into several pieces    -   (E) tablet has been pulverized

The results are shown in the table here below:

I-1 I-2 I-3 I-4 C-1 (D) (D) (D) (C) (A)

h) Tamper Resistance Grindability

The tablets were treated by means of o commercially available householdcoffee mill, type Bosch MKM6000 (180 W, type KM 13). Subsequently, thethus obtained material was analyzed by means of a sieving tower (Haver &Boecker, analysis sieve, diameter: 50 mm) equipped with a bottom plate,displacement ring, lid, and 14 sieves the mesh sizes ranging from 0.045mm to 4.000 mm, namely 0.045 mm; 0.063 mm; 0.090 mm; 0.125 mm; 0.180 mm;0.250 mm; 0.355 mm; 0.500 mm; 0.710 mm; 1.000 mm; 1.400 mm; 2.000 mm;2.800 mm; 4.000 mm. The amplitude was set to 1.5 mm. Sieving time was 10min.

The results after 2 minutes grinding are summarized in the table herebelow:

2 min grinding time I-1 I-2 I-3 I-4 C-1 <0.045 0.00 0.00 0.00 0.00 0.000.045-0.063 0.00 0.00 0.00 0.00 0.00 0.063-0.090 0.00 0.00 0.00 0.000.00 0.090-0.125 0.57 0.00 0.00 0.00 0.00 0.125-0.180 0.57 0.00 0.000.00 0.00 0.180-0.250 4.14 1.20 1.27 1.60 0.00 0.250-0.355 9.05 5.844.69 1.60 1.42 0.355-0.500 12.82 10.48 7.04 3.78 1.42 0.500-0.710 16.8114.09 12.26 5.48 3.72 0.710-1.000 15.72 15.29 14.05 7.18 6.561.000-1.400 15.20 19.45 15.26 11.00 14.54 1.400-2.000 12.53 16.17 17.2416.47 27.42 2.000-2.800 7.44 9.27 19.45 12.59 16.60 2.800-4.000 2.968.20 6.09 12.32 16.97 >4.000 2.19 0.00 2.65 28.00 11.35

It is clear from the above data that the dosage forms according to theinvention have advantages compared to the reference with respect toextractability in cold and hot water. At the same time, breakingstrength, impact resistance and indifference of the release profile topH changes of some preferred dosage forms according to the invention arecomparable to those of the reference.

EXAMPLE 2

Tablets having a total weight of 600 mg were manufactured in analogy toexample 1. The breaking strength (measured in accordance with WO2005/016313, WO 2005/016314, and WO 2006/082099) of the tablets wasmeasured (average value, n=3). The compositions and the measuredbreaking strengths are summarized in the table here below:

breaking (CBP + LUT): CBP: LUT: (CBP + LUT): API: API: API: ex. strength[N] CBP:LUT PEG PEG PEG HPMC (CBP + LUT) CBP LUT 2-1 565 1.0 4.0 2.0 2.05.6 0.4 0.7 0.7 2-2 1500 2.0 4.0 2.7 2.7 5.6 0.4 0.5 1.1 2-3 950 1.5 2.01.2 1.2 4.7 0.4 0.7 1.1 2-4 1500 1.5 3.0 1.8 1.8 5.3 0.4 0.6 1.0 2-51500 1.5 5.0 3.0 3.0 5.8 0.3 0.6 0.9 2-6 1500 1.5 6.0 3.6 3.6 6.0 0.30.6 0.8 2-7 1500 1.5 4.1 2.5 2.5 6.2 0.2 0.4 0.5 2-8 1500 1.5 4.0 2.42.4 — 0.3 0.5 0.8 2-9 1500 1.5 4.0 2.4 2.4 5.6 0.4 0.6 0.9 2-10 1500 1.54.0 2.4 2.4 2.4 0.4 0.7 1.0 2-11 1500 1.5 4.0 2.4 2.4 6.8 0.1 0.1 0.22-12 317 1.5 4.0 2.4 2.4 4.0 1.0 1.7 2.5 2-13 337 1.5 0.4 0.2 0.2 2.42.5 4.2 6.3 min. 1.0 0.4 0.2 0.2 2.4 0.1 0.1 0.2 max. 2.0 6.0 3.6 3.66.8 2.5 4.2 6.3 CBP = Carbopol 71 G LUT = Poloxamer 188 (Lutrol ® F68)PEG = Polyethylene glycol (Macrogol 6,000) HPMC =hydroxypropylmethylcellulose (HPMC 100,000) API = active pharmaceuticalingredient (Tramadol HCl)

1. A pharmaceutical dosage form having a breaking strength of at least300 N and comprising a pharmacologically active compound, an anionicpolymer bearing carboxylic groups, wherein the content of the anionicpolymer is 20 wt.-%, based on the total weight of the pharmaceuticaldosage form, and a nonionic surfactant.
 2. The pharmaceutical dosageform according to claim 1, wherein the anionic polymer is obtainable bypolymerization of a monomer composition comprising an ethylenicallyunsaturated monomer selected from ethylenically unsaturated carboxylicacids, ethylenically unsaturated carboxylic acid anhydrides,ethylenically unsaturated sulfonic acids, and mixtures thereof.
 3. Thepharmaceutical dosage form according to claim 1, wherein the anionicpolymer is derived from an ethylenically unsaturated monomer selectedfrom (alk)acrylic acids, (alk)acrylic anhydrides, alkyl (alk)acrylates,or a combination thereof.
 4. The pharmaceutical dosage form according toclaim 2, wherein the monomer composition further comprises at least onecross-linking agent selected from the group consisting of allyl sucrose,allyl pentaerythritol, divinyl glycol, divinyl polyethylene glycol and(meth)acrylic acid esters of diols.
 5. The pharmaceutical dosage formaccording to claim 1, which either does not contain any polyalkyleneoxide having an average molecular weight of at least 200,000 g/mol, orwherein the total content of polyalkylene oxide(s) having an averagemolecular weight of at least 200,000 g/mol is ≦35 wt.-%, based on thetotal weight of the pharmaceutical dosage form.
 6. The pharmaceuticaldosage form according to claim 1, wherein the pharmacologically activecompound is an opioid.
 7. The pharmaceutical dosage form according toclaim 1, wherein the nonionic surfactant (i) in pure water at aconcentration of 25 wt.-% forms an aqueous dispersion having a viscosityη₁ at a temperature of 20° C. and a viscosity η₂ at a temperature ofmore than 20° C., where η₂>η₁; and/or (ii) has an HLB value of at least20, and/or (iii) has a surface tension in 0.1% aqueous solution at 30°C. of at least 35 dynes/cm; and/or (iv) has a viscosity of at most 4000mPa·s, measured at 70° C. using a model LVF or LVT Brookfieldviscosimeter.
 8. The pharmaceutical dosage form according to claim 1,wherein the nonionic surfactant is a synthetic copolymer of ethyleneoxide and propylene oxide.
 9. The pharmaceutical dosage form accordingto claim 1, wherein the nonionic surfactant is selected from blockcopolymers according to general formula (I-a)

wherein a and c are each independently an integer of from 5 to 300, andb is an integer of from 10 to 100; and/or block copolymers according togeneral formula (I-b)

wherein e, f, g and h are each independently an integer of from 1 to150, and i, j, k and l are each independently an integer of from 2 to50.
 10. The pharmaceutical dosage form according to claim 1, wherein thecontent of the nonionic surfactant is at least 10 wt.-%, based on thetotal weight of the pharmaceutical dosage form.
 11. The pharmaceuticaldosage form according to claim 1, wherein the pharmacologically activecompound is embedded in a prolonged release matrix comprising theanionic polymer and the optionally present nonionic surfactant.
 12. Thepharmaceutical dosage form according to claim 1, which is configured foradministration once daily or twice daily.
 13. The pharmaceutical dosageform according to claim 1, which is thermoformed.
 14. The pharmaceuticaldosage form according to claim 1, which is tamper-resistant.
 15. Amethod of treating pain in a patient in need thereof, said methodcomprising administering to said patient a dosage form according toclaim 6.